miR-490-5p在膀胱癌中表达的临床意义及对膀胱癌细胞生物学特性影响的实验研究
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摘要
膀胱癌是我国泌尿生殖系统最常见的恶性肿瘤,发病率和死亡率均位居泌尿系统肿瘤的首位,严重危害我国人民的生命和健康。临床上对于膀胱癌的治疗策略主要是采用手术切除为主,辅以灌注化疗和免疫治疗的综合治疗,但效果不理想。寻找膀胱癌的发病基因,了解膀胱癌的分子遗传学机制,为膀胱癌的诊疗提供理论基础是目前的研究热点。
MicroRNA (miRNA)是在真核生物中发现的一类内源性的具有调控功能的非编码单链小分子RNA,大小约22个核苷酸,通常在转录后水平调控基因表达。大量研究表明,miRNA参与肿瘤细胞的增殖、分化、侵袭、转移及凋亡等各个环节。MiRNA具有高度的保守性、时序性和组织特异性等特点,预示它们可能是在一个新发现层次上的基因表达调控方式。miRNA的表达谱可作为肿瘤诊断和预后的指标,对其机制的深入探讨有望为膀胱癌诊疗提供新的思路和靶点。
miR-490-5p是新近发现的一种在肿瘤中异常表达的重要的microRNA。初步研究发现,其在包括膀胱癌在内的多种恶性肿瘤中表达显著下调,我们推测其在膀胱癌中发挥类似抑癌基因的功能。为了探索miR-490-5p与膀胱癌的关系,我们利用实时定量PCR技术检测其在膀胱癌、癌旁非肿瘤组织、膀胱癌细胞及正常膀胱细胞之间的表达,探讨其与患者临床分期及病理分级之间的关系。通过生物信息学预测、筛选miR-490-5p的靶基因,应用Western blot进行靶基因蛋白的验证。上调miR-490-5p的表达水平,研究其对膀胱癌细胞生物学行为的影响。进而探讨miR-490-5p在膀胱癌中可能的分子机制,以期为膀胱癌的早期诊断和治疗提供新的策略。
第一章miR-490-5p在膀胱癌组织和细胞中的表达及与临床分期、病理分级的关系研究
目的：研究miR-490-5p在膀胱癌组织和细胞中的表达及临床意义。
方法：采用实时定量PCR检测20例膀胱癌及其癌旁非肿瘤组织、3株膀胱癌细胞(T24、BIU-87和5637)和膀胱上皮永生化细胞(SV-HUC-1)中miR-490-5p的表达水平,研究其与临床分期、病理分级之间的关系。
结果：与配对的癌旁非肿瘤组织相比,癌组织中miR-490-5p的表达在所有样本中均下调。癌组织中miR-490-5p的相对表达量为1.175士0.643,癌旁非肿瘤组织中为8.539±1.920,两者表达有统计学差异(P<0.05)。20例膀胱癌组织标本中,根据临床分期分组,Ⅱ期miR-490-5p的相对表达量为1.149±0.677,Ⅲ-Ⅳ期为1-214±0.632,两者表达无显著差异(P>0.05)。根据病理分级分组,高分化组中miR-490-5p的相对表达量为1.770±0.452,中-低分化组中为0.688±0.206,两者表达有统计学差异(P<0.05)。正常膀胱细胞系SV-HUC-1中miR-490-5p的表达显著高于三种膀胱癌细胞(T24.5637、 BIU87)(P<0.05),且随着膀胱癌细胞恶性程度的增加,miR-490-5p的表达渐次降低(5637>BIU87>T24)。
结论：
1、膀胱癌组织中miR-490-5p的表达水平显著低于癌旁非肿瘤组织,提示miR-490-5p的表达下调可能与膀胱癌的发病机制有关。
2、膀胱癌组织中miR-490-5p的表达水平与患者临床分期无关。
3、膀胱癌组织中miR-490-5p的表达水平与病理分级相关,随病理分级的增加而降低。
4、miR-490-5p在三种膀胱癌细胞系中表达都显著低于膀胱上皮永生化细胞SV-HUC-1,其表达水平与膀胱癌细胞恶性程度有关,随细胞恶性程度的增高而降低。miR-490-5p在T24细胞中表达最低,据此选择该细胞系进行后续细胞功能实验及机制研究。
第二章膀胱癌组织和细胞中miR-490-5p靶基因筛选以及验证
目的：通过生物信息学检索,预测miR-490-5p的靶基因,并对这些靶基因进行验证
方法：通过miRBase.TargetScan和miRanda三个数据库进行检索,筛选miR-490-5p潜在的靶基因：c-Fos、TET1和UVRAG。从实验一结果中选择miR-490-5p表达最低的6例膀胱癌组织、癌旁非肿瘤组织及4株膀胱细胞,进行Western Blot检测,对这三个靶基因的蛋白表达水平进行验证。
结果：同膀胱癌旁非肿瘤组织相比,c-Fos蛋白的含量在膀胱癌组织中显著上调(P<0.05),UVRAG的含量显著下调(P<0.05),而TET1在两组间无显著差异(P>0.05)；同正常膀胱细胞相比,c-Fos蛋白的含量在膀胱癌细胞中显著上调(P<0.05),UVRAG的含量显著下调(P<0.05),而TET1无显著差异(P>0.05)。
结论：
1、miR-490-5p在膀胱癌中发挥着类似“抑癌基因”的作用,其缺失或表达水平下调会导致膀胱癌细胞生长分化,提示其有可能成为膀胱癌基因治疗的又一靶点。
2、c-Fos和UVRAG可能是miR-490-5p的靶基因,其对膀胱癌的影响可能通过这两个靶基因发挥作用。
第三章miR-490-5p对人膀胱癌T24细胞增殖、侵袭及凋亡影响的实验研究及机制探讨
目的：研究上调miR-490-5p表达对膀胱癌细胞T24生物学行为的影响及机制。
方法：
1、外源性转染miR-490-5p使T24细胞中miR-490-5p表达升高,同时分三组实验：正常组、阴性对照组(转染无意义的mimics)和转染目的miR-490-5p mimics组。
2、MTT实验绘制细胞生长曲线,评价miR-490-5p对T24细胞增殖能力的影响。
3、Transwell侵袭实验检测各组细胞侵袭能力,评价miR-490-5p对T24细胞侵袭能力的影响。
4、Caspase-3方法检测各组细胞凋亡情况,评价miR-490-5p对T24细胞凋亡的影响。
5、Western blot检测c-Fos和UVRAG的表达情况,探讨miR-490-5p对膀胱癌影响的机制。
结果：
1、实时PCR检测结果显示,转染miR-490-5p mimics组T24中miR-490-5p的表达量显著高于阴性对照组(P<0.05)。
2、转染miR-490-5p mimics组T24细胞的细胞存活率在48h和72h较阴性对照组低,差异具有显著性(P<0.05)。
3、转染miR-490-5p mimics组细胞侵袭数明显低于正常组和阴性对照组,差异具有显著性(P<0.05)。
4、Caspase-3酶活力在各组中的情况：正常组为(14.761±1.303)U/mg,阴性对照组为(15.719±1.613)U/mg,转染miR-490-5p mimics组为(43.615±4.399)U/mg。正常组和阴性对照组无显著差异(P>0.05),而转染miR-490-5p mimics组的Caspase-3酶活力显著高于正常组和阴性对照组(P<0.05)。
5、转染miR-490-5p mimics组中的c-Fos蛋白表达水平较正常组和阴性对照组显著下降,而UVRAG蛋白表达水平却显著增加(P<0.05)。
结论：
1、体外细胞实验中,膀胱癌细胞成功导入外源性高miR-490-5p可显著抑制T24细胞的增殖和侵袭能力,促进T24细胞凋亡。
2、miR-490-5p通过转录后水平调控c-Fos和UVRAG的表达,影响膀胱癌细胞的增殖、侵袭和凋亡
Bladder cancer, with the highest morbidity and mortality among the urinary system tumors, is one of the most common malignant neoplasms of the urinary system in China, which threatens people's life and health severely. The clinical treatment strategies for bladder cancer is mainly surgical excision, combined with infusion chemotherapy and immunotherapy treatments, which has unsatisfactory results.Find the incidence of bladder cancer gene to understand the molecular genetics of bladder cancer, and provide a theoretical basis for the diagnosis and treatment of bladder cancer is the research focus of the current.
MicroRNA is a class of small noncoding single-stranded RNAs found in eukaryotes, about22nucleotides in length, which usually regulates gene expression at the post-transcriptional level. A large number of studies have shown that microRNA participate in tumor cell proliferation, differentiation, invasion and apoptosis. MiRNA are highly conservative, timing and tissue-specific, which indicate that they may be in a new level of gene expression regulation. MiRNA expression profiles can be indicators as a tumor diagnosis and prognosis, and its mechanism of depth is expected to provide new ideas and targets for bladder cancer diagnosis and treatment.
miR-490-5p is a newly discovered abnormal expression microRNA in tumors, which has been found in a low level expression in a variety of malignancies including bladder cancer, so we hypothesized that it function as a tumor-supprissive gene.The miR-490-5p expression in bladder cancer and adjacent tissues, three types of bladder cancer cells and normal bladder epithelial cells will be detected by real-time PCR in our project, to explore its relationship with the clinical stage and histological grade. The study will make use of bioinformatics to predict and screen target genes of miR-490-5p, and validate them by Western blot.And then studymiR-490-5p's influence on the biological behavior of a bladder cancer cell. We hope to clarify the possible molecular mechanisms of miR-490-5p on bladder cancer, so as to provide new strateges on early diagnosis and treatment of bladder cancer.
Part I The expression of miR-490-5p and correlation with clinical stage and pathological grade of bladder cancer
Objective:To study the expression of miR-490-5p in bladder cancer and clinical significance.
Methods:The expression of miR-490-5p was detected by Real-time PCR in20cases of bladder cancer, adjacent non-tumor tissues, three bladder cancer cell lines (T24, BIU-87and5637) and bladder epithelial immortalized cell (SV-HUC-1).The relationship of miR-490-5p with clinical stage and pathological grade was also studied.
Results:The expression of miR-490-5p was down-regulated in20samples compared with paired adjacent non-tumor tissue. The relative expression level of miR-490-5p in bladder cancer was1.175±0.643, which was significantly lower than that in the adjacent non-tumor tissue with8.539±1.920(P<0.05).According to the clinical stage, the relative expression level of miR-490-5p was1.149±0.677in Ⅱ phase, and1.214±0.632in Ⅲ-Ⅳ phase, which had no significant difference(P>0.05).According to the pathological grade, the relative expression level of miR-490-5p in well-differentiated group was1.770±0.452, which was significantly higher than that in low-moderately differentiated group with0.688±0.206(P<0.05).The miR-490-5p expression in normal bladder cell line SV-HUC-1was significantly higher than that in the three bladder cancer cell lines (T24, BIU87and5637)(P<0.05), and it gradually decreased (5637> BIU87> of T24) with increasing degree of malignancy of bladder cancer cells.
Conclusion:
1. The expression of miR-490-5pin bladder cancer was significantly lower than that in adjacent non-tumor tissue, indicating it may be associated with the pathogenesis of bladder cancer.
2. The expression of miR-490-5p has no significant correlation with clinical stage in bladder cancer.
3. The expression of miR-490-5p has significant correlation with pathological grade, and it gradually decreases with increasing degree of pathological grade in bladder cancer.
4. The expression of miR-490-5p in the three bladder cancer cell lines was significantly lower than that in normal bladder cell line SV-HUC-1, and it gradually decreased with increasing degree of malignancy of bladder cancer cells. The expression of miR-490-5p was lowest in T24, and it was selected for further experiment.
Part Ⅱ The target gene screen and verification of miR-490-5p in bladder cancer tissues and cells
Objective:To predict and screen target genes of miR-490-5pby bioinformatics, and validate them by Western blot.
Methods:By searching databases of miRBase, TargetScan and miRanda.three miR-490-5p potential target genes were selected:c-Fos, TET1and UVRAG. Western blot was used to detect and validate the protein expression levels of these target genes in six cases withlowest expression ofmiR-490-5p, adjacent non-tumor tissue and four bladder cells.
Results:Compared with adjacent non-tumor tissue of bladder cancer, c-Fos protein level in bladder cancer significantly upregulated, UVRAG significantly reduced, while TET1with no significant difference between the two groups (P<0.05). Similarly, c-Fos protein level in bladder cancer was significantly upregulated, UVRAG significantly reduced, while TET1with no significant difference compared with normal bladder cells (P<0.05).
Conclusion:
1. miR-490-5p in bladder cancer plays a similar role of tumor suppressor gene, and its deletion or low expression will lead to bladder cancer cell growth and differentiation, suggesting that it may become another target for bladder cancer gene therapy.
2. c-Fos and UVRAG are the candidate target genes of miR-490-5p. miR-490-5p might have exert its impact on bladder cancer through these two target genes.
Part Ⅲ Effects of miR-490-5pon cell proliferation, invasion, and apoptosis of human bladder cancer T24cell
Objective:To study the effects of miR-490-5p high expression on bilogical characters of bladder cancer T24cell.
Methods:
1. miR-490-5p expression was increased in T24cell by exogenous transfection, and the experiment were divided into three groups:the normal group, negative control group (transfected meaningless mimics) and group of transfected miR-490-5p mimics.
2. MTT assay was employed to draw cell growth inhibition curvesand evaluate miR-490-5p's impact on the ability of T24cell proliferation.
3.Transwell invasion assay was used to determine the miR-490-5p' sinfluence on the ability of T24cell invasion.
4.Caspase-3was detected in each group to evaluate miR-490-5p's influence on the apoptosis of T24cell.
5. c-Fos and UVRAG were detected by Western blot to study the mechanism of miR-490-5p in bladder cancer.
Results:
1. Real-time PCR results showed that the expression of miR-490-5p in transfected miR-490-5p mimics group was significantly higher than that in the negative control group (P<0.05).
2. The rate of T24cell survivalin transfected miR-490-5p mimics group were significantly lower when compared with the negative control group at48h and72hafter transfection (P<0.05).
3. Transwell invasion assayshowed that the number of T24invasion in transfected miR-490-5p mimics group were significantly lower than that in the other groups (P<0.05).
4. The caspase-3level in each group were as follows:(14.761±1.303) U/mg in normal control group,(15.719±1.613)U/mg in negative control group (15.719±1.613)U/mg, and (43.615±4.399) U/mg in transfection of miR-490-5p mimics group. There was no significant differences between the normal group and the negative control group (P>0.05). The caspase-3levelin transfection of miR-490-5p mimics group was significantly higher than tha in the normal group and negative control group (P<0.05).
5. compared with the normal group and negative control group, the c-Fos protein level in ransfected miR-490-5p mimics group decreased significantly, while UVRAG increased significantly(P<0.05).
Conclusion:
1. In vitro experiments, the bladder cancer cell successfully imported by exogenous miR-490-5p can significantly inhibit proliferation and invasion, and promote apoptosis of T24cells.
2. miR-490-5p exerted imapact on the proliferation, invasion and apoptosis of bladder cancer cells by regulation of c-Fos and UVRAG at post-transcriptional level.
MicroRNA (miRNA)是在真核生物中发现的一类内源性的具有调控功能的非编码单链小分子RNA,大小约22个核苷酸,通常在转录后水平调控基因表达。大量研究表明,miRNA参与肿瘤细胞的增殖、分化、侵袭、转移及凋亡等各个环节。MiRNA具有高度的保守性、时序性和组织特异性等特点,预示它们可能是在一个新发现层次上的基因表达调控方式。miRNA的表达谱可作为肿瘤诊断和预后的指标,对其机制的深入探讨有望为膀胱癌诊疗提供新的思路和靶点。
miR-490-5p是新近发现的一种在肿瘤中异常表达的重要的microRNA。初步研究发现,其在包括膀胱癌在内的多种恶性肿瘤中表达显著下调,我们推测其在膀胱癌中发挥类似抑癌基因的功能。为了探索miR-490-5p与膀胱癌的关系,我们利用实时定量PCR技术检测其在膀胱癌、癌旁非肿瘤组织、膀胱癌细胞及正常膀胱细胞之间的表达,探讨其与患者临床分期及病理分级之间的关系。通过生物信息学预测、筛选miR-490-5p的靶基因,应用Western blot进行靶基因蛋白的验证。上调miR-490-5p的表达水平,研究其对膀胱癌细胞生物学行为的影响。进而探讨miR-490-5p在膀胱癌中可能的分子机制,以期为膀胱癌的早期诊断和治疗提供新的策略。
第一章miR-490-5p在膀胱癌组织和细胞中的表达及与临床分期、病理分级的关系研究
目的：研究miR-490-5p在膀胱癌组织和细胞中的表达及临床意义。
方法：采用实时定量PCR检测20例膀胱癌及其癌旁非肿瘤组织、3株膀胱癌细胞(T24、BIU-87和5637)和膀胱上皮永生化细胞(SV-HUC-1)中miR-490-5p的表达水平,研究其与临床分期、病理分级之间的关系。
结果：与配对的癌旁非肿瘤组织相比,癌组织中miR-490-5p的表达在所有样本中均下调。癌组织中miR-490-5p的相对表达量为1.175士0.643,癌旁非肿瘤组织中为8.539±1.920,两者表达有统计学差异(P<0.05)。20例膀胱癌组织标本中,根据临床分期分组,Ⅱ期miR-490-5p的相对表达量为1.149±0.677,Ⅲ-Ⅳ期为1-214±0.632,两者表达无显著差异(P>0.05)。根据病理分级分组,高分化组中miR-490-5p的相对表达量为1.770±0.452,中-低分化组中为0.688±0.206,两者表达有统计学差异(P<0.05)。正常膀胱细胞系SV-HUC-1中miR-490-5p的表达显著高于三种膀胱癌细胞(T24.5637、 BIU87)(P<0.05),且随着膀胱癌细胞恶性程度的增加,miR-490-5p的表达渐次降低(5637>BIU87>T24)。
结论：
1、膀胱癌组织中miR-490-5p的表达水平显著低于癌旁非肿瘤组织,提示miR-490-5p的表达下调可能与膀胱癌的发病机制有关。
2、膀胱癌组织中miR-490-5p的表达水平与患者临床分期无关。
3、膀胱癌组织中miR-490-5p的表达水平与病理分级相关,随病理分级的增加而降低。
4、miR-490-5p在三种膀胱癌细胞系中表达都显著低于膀胱上皮永生化细胞SV-HUC-1,其表达水平与膀胱癌细胞恶性程度有关,随细胞恶性程度的增高而降低。miR-490-5p在T24细胞中表达最低,据此选择该细胞系进行后续细胞功能实验及机制研究。
第二章膀胱癌组织和细胞中miR-490-5p靶基因筛选以及验证
目的：通过生物信息学检索,预测miR-490-5p的靶基因,并对这些靶基因进行验证
方法：通过miRBase.TargetScan和miRanda三个数据库进行检索,筛选miR-490-5p潜在的靶基因：c-Fos、TET1和UVRAG。从实验一结果中选择miR-490-5p表达最低的6例膀胱癌组织、癌旁非肿瘤组织及4株膀胱细胞,进行Western Blot检测,对这三个靶基因的蛋白表达水平进行验证。
结果：同膀胱癌旁非肿瘤组织相比,c-Fos蛋白的含量在膀胱癌组织中显著上调(P<0.05),UVRAG的含量显著下调(P<0.05),而TET1在两组间无显著差异(P>0.05)；同正常膀胱细胞相比,c-Fos蛋白的含量在膀胱癌细胞中显著上调(P<0.05),UVRAG的含量显著下调(P<0.05),而TET1无显著差异(P>0.05)。
结论：
1、miR-490-5p在膀胱癌中发挥着类似“抑癌基因”的作用,其缺失或表达水平下调会导致膀胱癌细胞生长分化,提示其有可能成为膀胱癌基因治疗的又一靶点。
2、c-Fos和UVRAG可能是miR-490-5p的靶基因,其对膀胱癌的影响可能通过这两个靶基因发挥作用。
第三章miR-490-5p对人膀胱癌T24细胞增殖、侵袭及凋亡影响的实验研究及机制探讨
目的：研究上调miR-490-5p表达对膀胱癌细胞T24生物学行为的影响及机制。
方法：
1、外源性转染miR-490-5p使T24细胞中miR-490-5p表达升高,同时分三组实验：正常组、阴性对照组(转染无意义的mimics)和转染目的miR-490-5p mimics组。
2、MTT实验绘制细胞生长曲线,评价miR-490-5p对T24细胞增殖能力的影响。
3、Transwell侵袭实验检测各组细胞侵袭能力,评价miR-490-5p对T24细胞侵袭能力的影响。
4、Caspase-3方法检测各组细胞凋亡情况,评价miR-490-5p对T24细胞凋亡的影响。
5、Western blot检测c-Fos和UVRAG的表达情况,探讨miR-490-5p对膀胱癌影响的机制。
结果：
1、实时PCR检测结果显示,转染miR-490-5p mimics组T24中miR-490-5p的表达量显著高于阴性对照组(P<0.05)。
2、转染miR-490-5p mimics组T24细胞的细胞存活率在48h和72h较阴性对照组低,差异具有显著性(P<0.05)。
3、转染miR-490-5p mimics组细胞侵袭数明显低于正常组和阴性对照组,差异具有显著性(P<0.05)。
4、Caspase-3酶活力在各组中的情况：正常组为(14.761±1.303)U/mg,阴性对照组为(15.719±1.613)U/mg,转染miR-490-5p mimics组为(43.615±4.399)U/mg。正常组和阴性对照组无显著差异(P>0.05),而转染miR-490-5p mimics组的Caspase-3酶活力显著高于正常组和阴性对照组(P<0.05)。
5、转染miR-490-5p mimics组中的c-Fos蛋白表达水平较正常组和阴性对照组显著下降,而UVRAG蛋白表达水平却显著增加(P<0.05)。
结论：
1、体外细胞实验中,膀胱癌细胞成功导入外源性高miR-490-5p可显著抑制T24细胞的增殖和侵袭能力,促进T24细胞凋亡。
2、miR-490-5p通过转录后水平调控c-Fos和UVRAG的表达,影响膀胱癌细胞的增殖、侵袭和凋亡
Bladder cancer, with the highest morbidity and mortality among the urinary system tumors, is one of the most common malignant neoplasms of the urinary system in China, which threatens people's life and health severely. The clinical treatment strategies for bladder cancer is mainly surgical excision, combined with infusion chemotherapy and immunotherapy treatments, which has unsatisfactory results.Find the incidence of bladder cancer gene to understand the molecular genetics of bladder cancer, and provide a theoretical basis for the diagnosis and treatment of bladder cancer is the research focus of the current.
MicroRNA is a class of small noncoding single-stranded RNAs found in eukaryotes, about22nucleotides in length, which usually regulates gene expression at the post-transcriptional level. A large number of studies have shown that microRNA participate in tumor cell proliferation, differentiation, invasion and apoptosis. MiRNA are highly conservative, timing and tissue-specific, which indicate that they may be in a new level of gene expression regulation. MiRNA expression profiles can be indicators as a tumor diagnosis and prognosis, and its mechanism of depth is expected to provide new ideas and targets for bladder cancer diagnosis and treatment.
miR-490-5p is a newly discovered abnormal expression microRNA in tumors, which has been found in a low level expression in a variety of malignancies including bladder cancer, so we hypothesized that it function as a tumor-supprissive gene.The miR-490-5p expression in bladder cancer and adjacent tissues, three types of bladder cancer cells and normal bladder epithelial cells will be detected by real-time PCR in our project, to explore its relationship with the clinical stage and histological grade. The study will make use of bioinformatics to predict and screen target genes of miR-490-5p, and validate them by Western blot.And then studymiR-490-5p's influence on the biological behavior of a bladder cancer cell. We hope to clarify the possible molecular mechanisms of miR-490-5p on bladder cancer, so as to provide new strateges on early diagnosis and treatment of bladder cancer.
Part I The expression of miR-490-5p and correlation with clinical stage and pathological grade of bladder cancer
Objective:To study the expression of miR-490-5p in bladder cancer and clinical significance.
Methods:The expression of miR-490-5p was detected by Real-time PCR in20cases of bladder cancer, adjacent non-tumor tissues, three bladder cancer cell lines (T24, BIU-87and5637) and bladder epithelial immortalized cell (SV-HUC-1).The relationship of miR-490-5p with clinical stage and pathological grade was also studied.
Results:The expression of miR-490-5p was down-regulated in20samples compared with paired adjacent non-tumor tissue. The relative expression level of miR-490-5p in bladder cancer was1.175±0.643, which was significantly lower than that in the adjacent non-tumor tissue with8.539±1.920(P<0.05).According to the clinical stage, the relative expression level of miR-490-5p was1.149±0.677in Ⅱ phase, and1.214±0.632in Ⅲ-Ⅳ phase, which had no significant difference(P>0.05).According to the pathological grade, the relative expression level of miR-490-5p in well-differentiated group was1.770±0.452, which was significantly higher than that in low-moderately differentiated group with0.688±0.206(P<0.05).The miR-490-5p expression in normal bladder cell line SV-HUC-1was significantly higher than that in the three bladder cancer cell lines (T24, BIU87and5637)(P<0.05), and it gradually decreased (5637> BIU87> of T24) with increasing degree of malignancy of bladder cancer cells.
Conclusion:
1. The expression of miR-490-5pin bladder cancer was significantly lower than that in adjacent non-tumor tissue, indicating it may be associated with the pathogenesis of bladder cancer.
2. The expression of miR-490-5p has no significant correlation with clinical stage in bladder cancer.
3. The expression of miR-490-5p has significant correlation with pathological grade, and it gradually decreases with increasing degree of pathological grade in bladder cancer.
4. The expression of miR-490-5p in the three bladder cancer cell lines was significantly lower than that in normal bladder cell line SV-HUC-1, and it gradually decreased with increasing degree of malignancy of bladder cancer cells. The expression of miR-490-5p was lowest in T24, and it was selected for further experiment.
Part Ⅱ The target gene screen and verification of miR-490-5p in bladder cancer tissues and cells
Objective:To predict and screen target genes of miR-490-5pby bioinformatics, and validate them by Western blot.
Methods:By searching databases of miRBase, TargetScan and miRanda.three miR-490-5p potential target genes were selected:c-Fos, TET1and UVRAG. Western blot was used to detect and validate the protein expression levels of these target genes in six cases withlowest expression ofmiR-490-5p, adjacent non-tumor tissue and four bladder cells.
Results:Compared with adjacent non-tumor tissue of bladder cancer, c-Fos protein level in bladder cancer significantly upregulated, UVRAG significantly reduced, while TET1with no significant difference between the two groups (P<0.05). Similarly, c-Fos protein level in bladder cancer was significantly upregulated, UVRAG significantly reduced, while TET1with no significant difference compared with normal bladder cells (P<0.05).
Conclusion:
1. miR-490-5p in bladder cancer plays a similar role of tumor suppressor gene, and its deletion or low expression will lead to bladder cancer cell growth and differentiation, suggesting that it may become another target for bladder cancer gene therapy.
2. c-Fos and UVRAG are the candidate target genes of miR-490-5p. miR-490-5p might have exert its impact on bladder cancer through these two target genes.
Part Ⅲ Effects of miR-490-5pon cell proliferation, invasion, and apoptosis of human bladder cancer T24cell
Objective:To study the effects of miR-490-5p high expression on bilogical characters of bladder cancer T24cell.
Methods:
1. miR-490-5p expression was increased in T24cell by exogenous transfection, and the experiment were divided into three groups:the normal group, negative control group (transfected meaningless mimics) and group of transfected miR-490-5p mimics.
2. MTT assay was employed to draw cell growth inhibition curvesand evaluate miR-490-5p's impact on the ability of T24cell proliferation.
3.Transwell invasion assay was used to determine the miR-490-5p' sinfluence on the ability of T24cell invasion.
4.Caspase-3was detected in each group to evaluate miR-490-5p's influence on the apoptosis of T24cell.
5. c-Fos and UVRAG were detected by Western blot to study the mechanism of miR-490-5p in bladder cancer.
Results:
1. Real-time PCR results showed that the expression of miR-490-5p in transfected miR-490-5p mimics group was significantly higher than that in the negative control group (P<0.05).
2. The rate of T24cell survivalin transfected miR-490-5p mimics group were significantly lower when compared with the negative control group at48h and72hafter transfection (P<0.05).
3. Transwell invasion assayshowed that the number of T24invasion in transfected miR-490-5p mimics group were significantly lower than that in the other groups (P<0.05).
4. The caspase-3level in each group were as follows:(14.761±1.303) U/mg in normal control group,(15.719±1.613)U/mg in negative control group (15.719±1.613)U/mg, and (43.615±4.399) U/mg in transfection of miR-490-5p mimics group. There was no significant differences between the normal group and the negative control group (P>0.05). The caspase-3levelin transfection of miR-490-5p mimics group was significantly higher than tha in the normal group and negative control group (P<0.05).
5. compared with the normal group and negative control group, the c-Fos protein level in ransfected miR-490-5p mimics group decreased significantly, while UVRAG increased significantly(P<0.05).
Conclusion:
1. In vitro experiments, the bladder cancer cell successfully imported by exogenous miR-490-5p can significantly inhibit proliferation and invasion, and promote apoptosis of T24cells.
2. miR-490-5p exerted imapact on the proliferation, invasion and apoptosis of bladder cancer cells by regulation of c-Fos and UVRAG at post-transcriptional level.
引文
[1]Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002. CA Cancer J Clin,2005,55(2):74-108.
[2]Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer,2010.
[3]Siegel R, Ward E, Brawley O, et al. Cancer statistics,2011:the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin,2011,61(4):212-36.
[4]虞颂庭,臧美孚,夏溟,吴阶平.吴阶平泌尿外科学.济南：山东科学技术出版社,2004：919-942.
[5]张薇,刘振伟,阮志贤,等.1973-1999年上海市区老年人恶性肿瘤发病趋势分析.中华老年医学杂志,2005,(09)：701-704.
[6]魏矿荣,梁智恒,林茂合.中山市1970-1999年膀胱癌发病趋势分析.中国肿瘤,2005,(04)：235-237.
[7]Parkin DM.The global health burden of infection-associated cancers in the year 2002. Int J Cancer,2006,118(12):3030-44.
[8]Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst,1995, 87(7):524-30.
[9]Kaldor JM, Day NE, Kittelmann B, et al. Bladder tumours following chemotherapy and radiotherapy for ovarian cancer:a case-control study. Int J Cancer.1905,63(1):1-6.
[10]Liou SH, Lung JC, Chen YH, et al. Increased chromosome-type chromosome aberration frequencies as biomarkers of cancer risk in a blackfoot endemic area. Cancer Res,1999,59(7):1481-4.
[11]林辉,宋建勇,熊鸿燕.饮水氯消毒暴露与膀胱癌联系的病例对照研究.中国公共卫生,2002,(04)：22-24.
[12]Sturgeon SR, Hartge P, Silverman DT, et al. Associations between bladder cancer risk factors and tumor stage and grade at diagnosis. Epidemiology,1994, 5(2):218-25.
[13]Piper JM, Tonascia J, Matanoski GM. Heavy phenacetin use and bladder cancer in women aged 20 to 49 years. N Engl J Med,1985,313(5):292-5.
[14]Kiemeney LA, Schoenberg M. Familial transitional cell carcinoma. J Urol,1996, 156(3):867-72.
[15]Czene K, Lichtenstein P, Hemminki K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int J Cancer,2002,99(2):260-6.
[16]Lynch CF, Cohen MB. Urinary system.Cancer,1995,75(1 Suppl):316-29.
[17]Mungan NA, Aben KK, Schoenberg MP, et al. Gender differences in stage-adjusted bladder cancer survival. Urology,2000,55(6):876-80.
[18]El-Bolkainy MN, Mokhtar NM, Ghoneim MA, et al. The impact of schistosomiasis on the pathology of bladder carcinoma.Cancer,1981, 48(12):2643-8.
[19]Fleshner NE, Herr HW, Stewart AK, et al. The national cancer data base report on bladder carcinoma. The American college of surgeons Commission on Cancer and the American Cancer Society. Cancer,1996,78(7):1505-13.
[20]Kantor AF, Hartge P, Hoover RN, et al. Epidemiological characteristics of squamous cell carcinoma and adenocarcinoma of the bladder. Cancer Res, 1988,48(13):3853-5.
[21]Waters WB. Invasive bladder cancer-where do we go from here. J Urol,996, 155(6):1910-1.
[22]van RBW, Burger M, Lotan Y, et al. Recurrence and progression of disease in non-muscle-invasive bladder cancer:from epidemiology to treatment strategy. Eur Urol, 2009,56(3):430-42.
[23]Stein JP, Quek ML, Skinner DG. Lymphadenectomy for invasive bladder cancer: I. historical perspective and contemporary rationale. BJU Int,2006, 97(2):227-31.
[24]Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer:long-term results in 1,054 patients. J Clin Oncol,2001, 19(3):666-75.
[25]Kuczyk M, Turkeri L, Hammerer P, et al. Is there a role for bladder preserving strategies in the treatment of muscle-invasive bladder cancer. Eur Urol,2003, 44(1):57-64.
[26]Shipley WU, Kaufman DS, Zehr E, et al. Selective bladder preservation by combined modality protocol treatment:long-term outcomes of 190 patients with invasive bladder cancer. Urology,2002,60(1):62-7; discussion 67-8.
[27]Liedberg F, Chebil G, Davidsson T, et al. Intraoperative sentinel node detection improves nodal staging in invasive bladder cancer. J Urol,2006,175(1):84-8; discussion 88-9.
[28]Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell,1993, 75(5):843-54.
[29]Reinhart BJ, Slack FJ, Basson M, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature,2000,403(6772):901-6.
[30]Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A,2002,99(24):15524-9.
[31]Kutay H, Bai S, Datta J, et al. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem,2006,99(3):671-8.
[32]Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A,2006, 103(7):2257-61.
[33]Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature,2005,435(7043):834-8.
[34]Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A,2006, 103(7):2257-61.
[35]Gottardo F, Liu CG, Ferracin M, et al. Micro-RNA profiling in kidney and bladder cancers. Urol Oncol,2007,25(5):387-92
[36]Lim LP, Lau NC, Garrett-Engele P, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature.2005. 433(7027):769-73.
[37]Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet,2009,10(10):704-14.
[38]Shi XB, Xue L, Yang J, et al. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci U S A,2007,104(50):19983-8.
[39]Takamizawa J, Konishi H, Yanagisawa K, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res,2004,64(11):3753-6.
[40]Chow TF, Mankaruos M, Scorilas A, et al. The miR-17-92 cluster is over expressed in and has an oncogenic effect on renal cell carcinoma. J Urol,2010, 183(2):743-51.
[41]Chiyomaru T, Enokida H, Tatarano S, et al. miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer. Br J Cancer.2010,102(5):883-91.
[42]Mao ZG, He DS, Zhou J, et al. Differential expression of microRNAs in GH-secreting pituitary adenomas.Diagn Pathol,2010,5:79.
[43]林茂松.人结直肠癌microRNA表达谱及其临床意义的研究：苏州大学,2010.
[44]Meiri E, Levy A, Benjamin H, et al. Discovery of microRNAs and other small RNAs in solid tumors. Nucleic Acids Res,2010,38(18):6234-46.
[45]Griffiths-Jones S. miRBase:microRNA sequences and annotation. Curr Protoc Bioinformatics,2010, Chapter 12:Unit 12.9.1-10.
[46]Pollack A, Wu CS, Czerniak B, et al. Abnormal bcl-2 and pRb expression are independent correlates of radiationresponse in muscle-invasive bladder cancer. Clin Cancer Res,1997,3(10):1823-9.
[47]Lipponen PK. Expression of c-myc protein is related to cell proliferation and expression ofgrowth factor receptors in transitional cell bladder cancer. J Pathol, 1995,175(2):203-10.
[48]Montie JE. CDC91L1 (PIG-U) is a newly discovered oncogene in human bladder cancer. J Urol,2005,174(3):869-70.
[49]van RBW, Lurkin I, Radvanyi F, et al. The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator ofsuperficial bladder cancer with low recurrence rate. Cancer Res,2001,61(4):1265-8.
[50]柳建军,苏劲.P53.C-erbB-2和bcl-2基因在膀胱癌中的表达及意义.临床泌尿外科杂志,2001,(08)：368-370.
[51]李和程,王子明.P53和MDM2基因表达及与膀胱癌生物学行为的关系.临床泌尿外科杂志,2001,(12)：526-528.
[52]Calin GA, Sevignani C, Dumitru CD, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A,2004,101(9):2999-3004.
[53]Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature,2005,435(7043):834-8.
[54]Huang Y, Dai Y, Yang J, et al. Microarray analysis of microRNA expression in renal clear cell carcinoma. Eur J Surg Oncol,2009,35(10):1119-23.
[55]Dyrskjot L, Ostenfeld MS, Bramsen JB, et al. Genomic profiling of microRNAs in bladder cancer:miR-129 is associated with pooroutcome and promotes cell death in vitro. Cancer Res,2009,69(11):4851-60.
[56]Yanaihara N, Caplen N, Bowman E, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell,2006,9(3):189-98.
[57]Liu CJ, Kao SY, Tu HF, et al. Increase of microRNA miR-31 level in plasma could be a potential marker of oralcancer. Oral Dis,2010,16(4):360-4.
[58]Hanke M, Hoefig K, Merz H, et al. A robust methodology to study urine microRNA as tumor marker:microRNA-126 andmicroRNA-182 are related to urinary bladder cancer. Urol Oncol,2010,28(6):655-61.
[59]Ng EK, Chong WW, Jin H, et al. Differential expression of microRNAs in plasma of patients with colorectalcancer:a potential marker for colorectal cancer screening. Gut,2009,58(10):1375-81.
[60]Catto JW, Abbod MF, Wild PJ, et al.The application of artificial intelligence to microarray data:identification of a novel gene signature to identify bladder cancer progression. Eur Urol,2010,57(3):398-406.
[61]Veerla S, Lindgren D, Kvist A, et al. MiRNA expression in urothelial carcinomas: important roles of miR-10a, miR-222,miR-125b, miR-7 and miR-452 for tumor stage and metastasis, and frequenthomozygous losses of miR-31. Int J Cancer, 2009,124(9):2236-42.
[62]Gregory RI, Shiekhattar R. MicroRNA biogenesis and cancer. Cancer Res,2005, 65(9):3509-12.
[63]Sevignani C, Calin GA, Siracusa LD, et al. Mammalian microRNAs:a small world for fine-tuning gene expression. Mamm Genome,2006,17(3):189-202.
[64]Miranda KC, Huynh T, Tay Y, et al. A pattern-based method for the identification of MicroRNA binding sites and theircorresponding heteroduplexes.Cell,2006, 126(6):1203-17.
[65]Saetrom O, Snove O Jr, Saetrom P. Weighted sequence motifs as an improved seeding step in microRNA targetprediction algorithms. RNA,2005, 11(7):995-1003.
[66]Saetrom P, Snove O Jr. Robust machine learning algorithms predict microRNA genes and targets. Methods Enzymol,2007,427:25-49.
[67]Ozen M, Creighton CJ, Ozdemir M, et al. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene,2008,27(12):1788-93.
[68]Markou A, Tsaroucha EG, Kaklamanis L, et al. Prognostic value of mature microRNA-21 and microRNA-205 overexpression innon-small cell lung cancer by quantitative real-time RT-PCR. Clin Chem,2008,54(10):1696-704.
[69]Zhu S, Si ML, Wu H, et al. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem,2007.282(19):14328-36.
[70]Tsang WP, Kwok TT. Epigallocatechin gallate up-regulation of miR-16 and induction of apoptosis inhuman cancer cells.J Nutr Biochem,2010,21(2):140-6.
[71]Kaddar T, Rouault JP, Chien WW, et al. Two new miR-16 targets:caprin-1 and HMGA1, proteins implicated in cellproliferation. Biol Cell,2009,101(9):511-24.
[72]Levin WJ, Press MF, Gaynor RB, et al. Expression patterns of immediate early transcription factors in human non-smallcell lung cancer. The lung cancer study group. Oncogene,1995,11(7):1261-9.
[73]Dunand-Sauthier I, Santiago-Raber ML, Capponi L, et al. Silencing of c-Fos expression by microRNA-155 is critical for dendritic cellmaturation and function. Blood,2011,117(17):4490-500.
[74]Lee HJ, Palkovits M,3rd YWS. miR-7b, a microRNA up-regulated in the hypothalamus after chronic hyperosmolarstimulation, inhibits Fos translation. Proc Natl Acad Sci U S A,2006,103(42):15669-74.
[75]Malaguarnera R, Vella V, Vigneri R, et al. p53 family proteins in thyroid cancer. Endocr Relat Cancer,2007,14(1):43-60.
[76]Yamasaki L. Role of the RB tumor suppressor in cancer. Cancer Treat Res,2003, 115:209-39.
[77]Liu J, Stevens J, Rote CA, et al. Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to theadenomatous polyposis coli protein. Mol Cell,2001, 7(5):927-36.
[78]Le MT, Teh C, Shyh-Chang N, et al. MicroRNA-125b is a novel negative regulator of p53. Genes Dev,2009,23(7):862-76.
[79]Cai K, Wang Y, Bao X. MiR-106b promotes cell proliferation via targeting RB in laryngeal carcinoma. J Exp Clin Cancer Res,2011,30:73.
[80]Liang C, Feng P, Ku B, et al. Autophagic and tumour suppressor activity of a novel Beclinl-binding proteinUVRAG Nat Cell Biol,2006,8(7):688-99.
[81]Lorsbach RB, Moore J, Mathew S, et al. TET1, a member of a novel protein family, is fused to MLL in acute myeloidieukemia containing the t(10;11)(q22;q23). Leukemia,2003,17(3):637-41.
[82]Ono R, Taki T, Taketani T, et al. LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acutemyeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). Cancer Res,2002,62(14):4075-80.
[83]Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLLpartner TET1. Science, 2009,324(5929):930-5.
[84]Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryoniclethality. Cell,1992,69(6):915-26.
[85]Dahl C, Gronbaek K, Guldberg P. Advances in DNA methylation: 5-hydroxymethylcytosine revisited. Clin Chim Acta,2011,412(11-12):831-6.
[86]Johnson SM, Grosshans H, Shingara J, et al. RAS is regulated by the let-7 microRNA family. Cell,2005,120(5):635-47.
[87]Akao Y, Nakagawa Y, Naoe T. let-7 microRNA functions as a potential growth suppressor in human colon cancercells. Biol Pharm Bull,2006,29(5):903-6.
[88]Takamizawa J, Konishi H, Yanagisawa K, et al. Reduced expression of the let-7 microRNAs in human lung cancers in associationwith shortened postoperative survival. Cancer Res,2004,64(11):3753-6.
[89]Jerome T, Laurie P, Louis B, et al. Enjoy the Silence:The Story of let-7 MicroRNA and Cancer. Curr Genomics,2007,8(4):229-33.
[90]Mayr C, Hemann MT, Bartel DP. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science,2007,315(5818):1576-9.
[91]Lee YS, Dutta A. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev,2007,21 (9):1025-30.
[92]Klemke M, Meyer A, Hashemi NM, et al. Loss of let-7 binding sites resulting from truncations of the 3'untranslatedregion of HMGA2 mRNA in uterine leiomyomas. Cancer Genet Cytogenet,2010,196(2):119-23.
[93]Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify buman cancers. Nature,2005,435(7043):834-8.
[94]Kawasaki H, Taira K. MicroRNA-196 inhibits HOXB8 expression in myeloid differentiation of HL60 cells. Nucleic Acids Symp Ser (Oxf),2004,(48):211-2.
[95]Eulalio A, Huntzinger E, Nishihara T, et al. Deadenylation is a widespread effect of miRNA regulation. RNA,2009,15(1):21-32.
[96]He L, Hannon GJ. MicroRNAs:small RNAs with a big role in gene regulation. Nat Rev Genet,2004,5(7):522-31.
[97]Kim VN. Small RNAs:classification, biogenesis, and function. Mol Cells,2005, 19(1):1-15.
[98]Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol,2009,4:199-227.
[99]Schmittgen TD. miR-31:a master regulator of metastasis. Future Oncol, 2010,6(1):17-20.
[100]Segura MF, Hanniford D, Menendez S, et al. Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proc Natl Acad Sci U S A,2009, 106(6):1814-9.
[101]Sotiropoulou G, Pampalakis G, Lianidou E, et al. Emerging roles of microRNAs as molecular switches in the integrated circuit ofthe cancer cell. RNA,2009, 15(8):1443-61.
[102]Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol,2009,4:199-227.
[103]Wong CM, Wong CC, Lee JM, et al. Sequential alterations of miRNA expression in hepatocellular carcinoma development and venous metastasis. LID-10.1002/hep.25512 [doi]. Hepatology,2011.
[104]Donnem T, Fenton CG, Lonvik K, et al. MicroRNA signatures in tumor tissue related to angiogenesis in non-small celllung cancer. PLoS One,2012, 7(1):e29671.
[105]Bovell L, Shanmugam C, Katkoori VR, et al. miRNAs are stable in colorectal cancer archival tissue blocks. Front Biosci (Elite Ed),2012,4:1937-40.
[106]Alshatwi AA, Shafi G, Hasan TN, et al. Differential Expression Profile and Genetic Variants of MicroRNAs Sequences inBreast Cancer Patients. PLoS One, 2012,7(2):e30049.
[107]Chen ZH, Zhang GL, Li HR, et al. A panel of five circulating microRNAs as potential biomarkers for prostatecancer.LID-10.1002/pros.22495 [doi]. Prostate, 2012.
[108]Costa FF, Bischof JM, Vanin EF, et al. Identification of microRNAs as potential prognostic markers in ependymoma. PLoS One,2011,6(10):e25114.
[109]Schmeier S, Schaefer U, Essack M, et al. Network analysis of microRNAs and their regulation in human ovarian cancer. BMC Syst Biol,2011,5:183.
[110]de Oliveira JC, Scrideli CA, Brassesco MS, et al. Differential miRNA expression in childhood acute lymphoblastic leukemia andassociation with clinical and biological features. Leuk Res,2012,36(3):293-8.
[111]Wang G, Chan ES, Kwan BC, et al. Expression of microRNAs in the urine of patients with bladder cancer. Clin Genitourin Cancer,2012.
[112]Song T, Xia W, Shao N, et al. Differential miRNA expression profiles in bladder urothelial carcinomas. Asian Pac J Cancer Prev,2010, 11(4):905-11.
[113]Xie P, Xu F, Cheng W, et al. Detection, verification and significance of differentially expressed miRNAs inbladder urothelial carcinoma. Zhonghua Yi Xue Za Zhi,2010,90(48):3391-4.
[114]Tuck AB, Park M, Sterns EE, et al. Coexpression of hepatocyte growth factor and receptor (Met) in human breastcarcinoma. Am J Pathol,1996, 148(1):225-32.
[115]Eis PS, Tam W, Sun L, et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A,2005,102(10):3627-32.
[116]Iorio MV, Ferracin M, Liu CG, et al. Micro RNA gene expression deregulation in human breast cancer. Cancer Res,2005,65(16):7065-70.
[117]Buechner J, Tomte E, Haug BH, et al. Tumour-suppressor microRNAs let-7 and mir-101 target the proto-oncogene MYCN and inhibit cell proliferation in MYCN-amplified neuroblastoma. Br J Cancer,2011,105(2):296-303.
[118]Wang V, Wu W. MicroRNA-based therapeutics for cancer. BioDrugs,2009, 23(1):15-23.
[119]Takeshita F, Patrawala L, Osaki M, et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther.2010,18(1):181-7.
[120]Braun J, Hoang-Vu C, Dralle H, et al. Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas. Oncogene, 2010,29(29):4237-44.
[121]Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition bytargeting ZEB1 and SIP1. Nat Cell Biol,2008,10(5):593-601.
[122]Park SM, Gaur AB, Lengyel E, et al. The miR-200 family determines the epithelial phenotype of cancer cells bytargeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev,2008,22(7):894-907.
[123]Nan Y, Han L, Zhang A, et al. MiRNA-451 plays a role as tumor suppressor in human glioma cells. Brain Res,2010,1359:14-21.
[124]Godlewski J, Nowicki MO, Bronisz A, et al. MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolicstress in glioma cells. Mol Cell,2010,37(5):620-32.
[125]Zhu S, Wu H, Wu F, et al. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res,2008,18(3):350-9.
[126]Bhaumik D, Scott GK, Schokrpur S, et al. Expression of microRNA-146 suppresses NF-kappaB activity with reduction ofmetastatic potential in breast cancer cells. Oncogene,2008,27(42):5643-7.
[127]Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature,2007,449(7163):682-8.
[128]Galardi S, Mercatelli N, Giorda E, et al. miR-221 and miR-222 expression affects the proliferation potential of humanprostate carcinoma cell lines by targeting p27Kipl. J Biol Chem,2007,282(32):23716-24.
[129]Liu Y, Wang HX, Lu N, et al. Translocation of annexin I from cellular membrane to the nuclear membrane inhuman esophageal squamous cell carcinoma. World J Gastroenterol,2003,9(4):645-9.
[130]Duncan R, Carpenter B, Main LC, et al. Characterisation and protein expression profiling of annexins in colorectaicancer. Br J Cancer,2008,98(2):426-33.
[131]Bai XF, Ni XG, Zhao P, et al. Overexpression of annexin 1 in pancreatic cancer and its clinical significance. World J Gastroenterol,2004,10(10):1466-70.
[132]Yang LP, Yang ZL, Tan XG, et al. Expression of annexin A1 (ANXA1) and A2 (ANXA2) and its significance in benignand malignant lesions of gallbladder. Zhonghua Zhong Liu Za Zhi,2010,32(8):595-9.
[133]Luthra R, Singh RR, Luthra MG, et al. MicroRNA-196a targets annexin A1:a microRNA-mediated mechanism of annexin A1downregulation in cancers. Oncogene,2008,27(52):6667-78.
[134]Si ML, Zhu S, Wu H, et al. miR-21-mediated tumor growth. Oncogene,2007, 26(19):2799-803.
[135]Kim S, Lee UJ, Kim MN, et al. MicroRNA miR-199a* regulates the MET proto-oncogene and the downstreamextracellular signal-regulated kinase 2 (ERK2). J Biol Chem,2008,283(26):18158-66.
[136]Johnson SM, Grosshans H, Shingara J, et al. RAS is regulated by the let-7 microRNA family. Cell,2005,120(5):635-47.
[137]Matsubara H, Takeuchi T, Nishikawa E, et al. Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20ain lung cancers overexpressing miR-17-92. Oncogene,2007,26(41):6099-105.
[138]Kondo N, Toyama T, Sugiura H, et al. miR-206 Expression is down-regulated in estrogen receptor alpha-positive humanbreast cancer. Cancer Res,2008, 68(13):5004-8.
[139]Meng F, Henson R, Wehbe-Janek H, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in humanhepatocellular cancer. Gastroenterology,2007,133(2):647-58.
[140]Fischer U, Janicke RU, Schulze-Osthoff K. Many cuts to ruin:a comprehensive update of caspase substrates. Cell Death Differ,2003,10(1):76-100.
[141]Dasmahapatra G, Almenara JA, Grant S. Flavopiridol and histone deacetylase inhibitors promote mitochondrial injury and cell death in human leukemia cells that overexpress Bcl-2. Mol Pharmacol,2006,69(1):288-98.
[142]Youssef AM, Malki A, Badr MH, et al. Synthesis and Anticancer Activity of Novel Benzimidazole and BenzothiazoleDerivatives against HepG2 Liver Cancer Cells. Med Chem,2012.
[143]Sato M, Tsujino I, Fukunaga M, et al. Cyclosporine A induces apoptosis of human lung adenocarcinoma cells viacaspase-dependent pathway. Anticancer Res,2011,31(6):2129-34.
[144]Wang J, Li Q, Ou Y, et al. Inhibition of tumor growth by recombinant adenovirus containing human lactoferrinthrough inducing tumor cell apoptosis in mice bearing EMT6 breast cancer. Arch Pharm Res,2011,34(6):987-95.
[145]Park C, Jin CY, Kim GY, et al. Induction of apoptosis by ethanol extract of Prunus mume in U937 human leukemiacells through activation of caspases. Oncol Rep,2011,26(4):987-93.
[146]Mishunina TM, Kalinichenko OV, Tronko MD, et al. Caspase-3 activity in papillary thyroid carcinomas. Exp Oncol,2010,32(4):269-72.
[147]Joo SS, Yoo YM. Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways:therapeutic implications for prostate cancer. J Pineal Res, 2009,47(1):8-14.
[148]Shen L, Zeng S, Chen J, et al. El A inhibits the proliferation of human cervical cancer cells (HeLa cells) byapoptosis induction through activation of HER-2/Neu/Caspase-3 pathway. Med Oncol,2008,25(2):222-8.
[149]Fang YX, Xue JL, Shen Q, et al. miR-7 inhibits tumor growth and metastasis by targeting the PI3K/AKT pathway inhepatocellular carcinoma.LID 10.1002/hep.25576 [doi]. Hepatology,2012.
[150]Ohdaira H, Sekiguchi M, Miyata K, et al. MicroRNA-494 suppresses cell proliferation and induces senescence in A549 lungcancer cells. Cell Prolif,2012, 45(1):32-8.
[151]Cai C, Ashktorab H, Pang X, et al. MicroRNA-211 expression promotes colorectal cancer cell growth in vitro and invivo by targeting tumor suppressor CHD5. PLoS One,2012,7(1):e29750.
[152]Akhavantabasi S, Sapmaz A, Tuna S, et al. miR-125b Targets ARID3B in Breast Cancer Cells. Cell Struct Funct,2012,37(1):27-38.
[153]Kojima S, Chiyomaru T, Kawakami K, et al. Tumour suppressors miR-1 and miR-133a target the oncogenic function of purinenucleoside phosphorylase (PNP) in prostate cancer. Br J Cancer,2012,106(2):405-13.
[154]Kovaleva V, Mora R, Park YJ, et al. MicroRNA-130a targets ATG2B and DICER1 to inhibit autophagy and trigger killingof chronic lymphocytic leukemia cells. Cancer Res,2012.
[155]O'Connor L, Strasser A, O'Reilly LA, et al. Bim:a novel member of the Bcl-2 family that promotes apoptosis. EMBO J,1998,17(2):384-95.
[156]Liu JW, Chandra D, Tang SH, et al. Identification and characterization of Bimgamma, a novel proapoptotic BH3-onlysplice variant of Bim. Cancer Res, 2002,62(10):2976-81.
[157]Sunters A, de Mattos S F, Stahl M, et al. FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treatedbreast cancer cell lines. J Biol Chem, 2003,278(50):49795-805.
[158]Zhang H, Zuo Z, Lu X, et al. MiR-25 regulates apoptosis by targeting Bim in human ovarian cancer. Oncol Rep,2012,27(2):594-8.
[159]Tatarano S, Chiyomaru T, Kawakami K, et al. Novel oncogenic function of mesoderm development candidate 1 and its regulationby MiR-574-3p in bladder cancer cell lines. Int J Oncol,2012,40(4):951-9.
[160]Yoshino H, Enokida H, Chiyomaru T, et al. Tumor suppressive microRNA-1 mediated novel apoptosis pathways through directinhibition of splicing factor serine/arginine-rich 9 (SRSF9/SRp30c) in bladdercancer. Biochem Biophys Res Commun,2012,417(1):588-93.
[161]Hirata H, Hinoda Y, Ueno K, et al. MicroRNA-1826 targets VEGFC, beta-catenin (CTNNB1) and MEK1 (MAP2K1) in humanbladder cancer. Carcinogenesis,2012,33(1):41-8.
[162]Ming J, Jiang G, Zhang Q, et al. Interleukin-7 up-regulates cyclin D1 via activator protein-1 to promoteproliferation of cell in lung cancer. Cancer Immunol Immunother,2012,61(1):79-88.
[163]Mahner S, Baasch C, Schwarz J, et al. C-Fos expression is a molecular predictor of progression and survival inepithelial ovarian carcinoma. Br J Cancer,2008, 99(8):1269-75.
[164]Lin YF, Wu MS, Chang CC, et al. Comparative immunoproteomics of identification and characterization of virulence factors from Helicobacter pylori related to gastric cancer. Mol Cell Proteomics,2006,5(8):1484-96.
[165]Vairaktaris E, Papakosta V, Derka S, et_al. H-ras and c-Fos exhibit similar expression patterns during most stages of oraloncogenesis. In Vivo,2008, 22(5):621-8.
[166]Baan B, Pardali E, ten DP, et al. In situ proximity ligation detection of c-Jun/AP-1 dimers reveals increasedlevels of c-Jun/Fral complexes in aggressive breast cancer cell lines in vitroand in vivo. Mol Cell Proteomics, 2010,9(9):1982-90.
[167]Yao HQ, Peng Y, Zhong ZZ, et al. Association of the expressions of platelet-derived growth factor receptor andc-Fos with the biological characteristics of bladder cancer. Di Yi Jun Yi Da Xue Xue Bao,2004, 24(2):177-9.
[168]Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer,2007,7(12):961-7.
[169]Maiuri MC, Tasdemir E, Criollo A, et al. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ,2009,16(1):87-93.
[170]Wu T, Li Y, Gong L, et al. Multi-step process of human breast carcinogenesis:a role for BRCA1, BECN1,CCND1, PTEN and UVRAG Mol Med Report, 2012,5(2):305-12.
[171]Thoresen SB, Pedersen NM, Liestol K, et al. A phosphatidylinositol 3-kinase class III sub-complex containing VPS 15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytictraffic. Exp Cell Res,2010, 316(20):3368-78.
[172]Takahashi Y, Coppola D, Matsushita N, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy andtumorigenesis. Nat Cell Biol, 2007,9(10):1142-51.
[173]Liang C, Feng P, Ku B, et al. UVRAG:a new player in autophagy and tumor cell growth. Autophagy,2007,3(1):69-71.
[174]Liang C, Lee JS, Inn KS, et al. Beclinl-binding UVRAG targets the class C Vps complex to coordinate autophagosomematuration and endocytic trafficking. Nat Cell Biol,2008,10(7):776-87.
[1]Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell,1993, 75(5):843-54.
[2]Reinhart BJ, Slack FJ, Basson M, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature,2000,403(6772):901-6.
[3]Lagos-Quintana M, Rauhut R, Lendeckel W, et al. Identification of novel genes coding for small expressed RNAs. Science,2001,294(5543):853-8.
[4]Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science,2001,294(5543):862-4.
[5]Ruvkun G. Molecular biology. Glimpses of a tiny RNA world. Science,2001, 294(5543):797-9.
[6]Lau NC, Lim LP, Weinstein EG, et al. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science,2001, 294(5543):858-62.
[7]Voinnet O. Origin, biogenesis, and activity of plant rnicroRNAs. Cell,2009, 136(4):669-87.
[8]Xiao C, Rajewsky K. MicroRNA control in the immune system:basic principles. Cell,2009,136(1):26-36.
[9]Chendrimada TP, Gregory RI, Kumaraswamy E, et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature,2005, 436(7051):740-4.
[10]Lee Y, Hur I, Park SY, et al. The role of PACT in the RNA silencing pathway.EMBO J,2006,25(3):522-32.
[11]Schaefer A, Jung M, Kristiansen G, et al. MicroRNAs and cancer:current state and future perspectives in urologic oncology. Urol Oncol,2010,28(1):4-13.
[12]Ruvkun G. Molecular biology. Glimpses of a tiny RNA world. Science,2001, 294(5543):797-9.
[13]Lau NC, Lim LP, Weinstein EG, et al. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science,2001, 294(5543):858-62.
[14]McDonald JS, Milosevic D, Reddi HV, et al. Analysis of circulating microRNA: preanalytical and analytical challenges. Clin Chem,2011,57(6):833-40.
[15]Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One,2008,3(9):e3148.
[16]Pasquinelli AE, Reinhart BJ, Slack F, et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature,2000, 408(6808):86-9.
[17]Lau NC, Lim LP, Weinstein EG, et al. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science,2001, 294(5543):858-62.
[18]Reinhart BJ, Weinstein EG, Rhoades MW, et al. MicroRNAs in plants. Genes Dev, 2002,16(13):1616-26.
[19]Chen CZ, Li L, Lodish HF, et al. MicroRNAs modulate hematopoietic lineage differentiation. Science,2004,303(5654):83-6.
[20]Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science,2001,294(5543):862-4.
[21]Lagos-Quintana M, Rauhut R, Lendeckel W, et al. Identification of novel genes coding for small expressed RNAs. Science,2001,294(5543):853-8.
[22]Johnson CD, Esquela-Kerscher A, Stefani G, et al. The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res,2007,67(16):7713-22.
[23]Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet,2009,10(10):704-14.
[24]Lim LP, Lau NC, Garrett-Engele P, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature,2005, 433(7027):769-73.
[25]Song JJ, Smith SK, Hannon GJ, et al. Crystal structure of Argonaute and its implications for RISC slicer activity. Science,2004,305(5689):1434-7.
[26]Liu J, Carmell MA, Rivas FV, et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science,2004,305(5689):1437-41.
[27]Wu L, Fan J, Belasco JG MicroRNAs direct rapid deadenylation of mRNA. Proc Natl Acad Sci U S A,2006,103(11):4034-9.
[28]Orom UA, Nielsen FC, Lund AH. MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell,2008,30(4):460-71.
[29]Flynt AS, Lai EC. Biological principles of microRNA-mediated regulation: shared themes amiddiversity. Nat Rev Genet,2008,9(11):831-42.
[30]Lim LP, Lau NC, Weinstein EG, et al.The microRNAs of Caenorhabditis elegans. Genes Dev,2003,17(8):991-1008.
[31]Sempere LF, Freemantle S, Pitha-Rowe I, et al. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol,2004, 5(3):R13.
[32]Castoldi M, Schmidt S, Benes V. et al. miChip:an array-based method for microRNA expression profiling using lockednucleic acid capture probes. Nat Protoc,2008,3(2):321-9.
[33]Chen C, Ridzon DA, Broomer AJ, et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res.2005,33(20):e179.
[34]Raymond CK, Roberts BS, Garrett-Engele P, et al. Simple, quantitative primer-extension PCR assay for direct monitoring ofmicroRNAs and short-interfering RNAs. RNA,2005,11 (11):1737-44.
[35]Zhang W, Dahlberg JE, Tam W. MicroRNAs in tumorigenesis:a primer. Am J Pathol,2007,171(3):728-38.
[36]Grundhoff A, Sullivan CS, Ganem D. A combined computational and microarray-based approach identifies novel microRNAsencoded by human gamma-herpesviruses. RNA,2006,12(5):733-50.
[37]Castoldi M, Schmidt S, Benes V, et al. miChip:an array-based method for microRNA expression profiling using lockednucleic acid capture probes. Nat Protoc,2008,3(2):321-9.
[38]Beuvink I, Kolb FA, Budach W, et al. A novel microarray approach reveals new tissue-specific signatures of known andpredicted mammalian microRNAs. Nucleic Acids Res,2007,35(7):e52.
[39]Hua YJ, Tu K, Tang ZY, et al. Comparison of normalization methods with microRNA microarray. Genomics,2008,92(2):122-8.
[40]Castoldi M, Schmidt S, Benes V, et al. A sensitive array for microRNA expression profiling (miChip) based on lockednucleic acids (LNA). RNA,2006, 12(5):913-20.
[41]Lagos-Quintana M, Rauhut R, Yalcin A, et al. Identification of tissue-specific microRNAs from mouse. Curr Biol,2002,12(9):735-9.
[42]'t HPA, Ariyurek Y, Thygesen HH, et al. Deep sequencing-based expression analysis shows major advances in robustness, resolution and inter-lab portability over five microarray platforms. Nucleic Acids Res,2008,36(21):e141.
[43]Szittya G, Moxon S, Santos DM, et al. High-throughput sequencing of Medicago truncatula short RNAs identifies eight newmiRNA families. BMC Genomics, 2008,9:593.
[44]Rathjen T, Pais H, Sweetman D, et al. High throughput sequencing of microRNAs in chicken somites. FEBS Lett,2009,583(9):1422-6.
[45]Glazov EA, Cottee PA, Barris WC, et al.A microRNA catalog of the developing chicken embryo identified by a deepsequencing approach. Genome Res,2008, 18(6):957-64.
[46]Chellappan P, Jin H. Discovery of plant microRNAs and short-interfering RNAs by deep parallelsequencing. Methods Mol Biol,2009,495:121-32.
[47]Morozova O, Marra MA. Applications of next-generation sequencing technologies in functional genomics. Genomics,2008,92(5):255-64.
[48]Wyman SK, Parkin RK, Mitchell PS, et al. Repertoire of microRNAs in epithelial ovarian cancer as determined by nextgeneration sequencing of small RNA cDNA libraries. PLoS One,2009,4(4):e5311.
[49]Hafner M, Landgraf P, Ludwig J, et al. Identification of microRNAs and other small regulatory RNAs using cDNA librarysequencing. Methods,2008, 44(1):3-12.
[50]Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A,2002,99(24):15524-9.
[51]Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A,2005,102(39):13944-9.
[52]Kutay H, Bai S, Datta J, et al. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem,2006,99(3):671-8.
[53]Roldo C, Missiaglia E, Hagan JP, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol,2006,24(29):4677-84.
[54]Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets, Proc Natl Acad Sci U S A,2006, 103(7):2257-61.
[55]Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature,2005,435(7043):834-8.
[56]Calin GA, Croce CM, MicroRNA signatures in human cancers. Nat Rev Cancer, 2006,6(11):857-66.
[57]Zhang B, Pan X, Cobb GP, et al. microRNAs as oncogenes and tumor suppressors. Dev Biol,2007,302(1):1-12.
[58]Esquela-Kerscher A, Slack FJ. Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer,2006,6(4):259-69.
[59]Hua S, Xiaotao X, Renhua G, et al. Reduced miR-31 and let-7 maintain the balance between differentiation andquiescence in lung cancer stem-like side population cells. Biomed Pharmacother,2012.
[60]Shimizu S, Takehara T, Hikita H, et al. The let-7 family of microRNAs inhibits Bcl-xL expression and potentiatessorafenib-induced apoptosis in human hepatocellular carcinoma. J Hepatol,2010,52(5):698-704.
[61]O'Day E, Lal A. MicroRNAs and their target gene networks in breast cancer. Breast Cancer Res,2010,12(2):201.
[62]Nishino J, Kim I, Chada K, et al. Hmga2 promotes neural stem cell self-renewal in young but not old mice byreducing p16Ink4a and p19Arf Expression. Cell, 2008,135(2):227-39.
[63]Yu F, Yao H, Zhu P, et al. let-7 regulates self-renewal and tumorigenicity of breast cancer cells. Cell,2007,131(6):1109-23.
[64]Takamizawa J, Konishi H, Yanagisawa K, et al. Reduced expression of the let-7 microRNAs in human lung cancers in associationwith shortened postoperative survival. Cancer Res,2004,64(11):3753-6.
[65]Fang WJ, Lin CZ, Zhang HH, et al. Detection of let-7a microRNA by real-time PCR in colorectal cancer:asingle-centre experience from China. J Int Med Res, 2007,35(5):716-23.
[66]Lee YS, Dutta A. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev,2007,21(9):1025-30.
[67]Liu Q, Lv GD, Qin X, et al. Role of microRNA let-7 and effect to HMGA2 in esophageal squamous cell carcinoma. Mol Biol Rep,2012,39(2):1239-46.
[68]Sampson VB, Rong NH, Han J, et al. MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkittlymphoma cells. Cancer Res,2007, 67(20):9762-70.
[69]Kumar MS, Lu J, Mercer KL, et al. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet,2007,39(5):673-7.
[70]Johnson SM, Grosshans H, Shingara J, et al. RAS is regulated by the let-7 microRNA family. Cell,2005,120(5):635-47.
[71]He XY, Chen JX, Zhang Z, et al. The let-7a microRNA protects from growth of lung carcinoma by suppression ofk-Ras and c-Myc in nude mice. J Cancer Res Clin Oncol,2010,136(7):1023-8.
[72]Garzon R, Calin GA, Croce CM. MicroRNAs in Cancer. Annu Rev Med,2009, 60:167-79.
[73]Park SY, Lee JH, Ha M, et al. miR-29 miRNAs activate p53 by targeting p85 alpha and CDC42. Nat Struct Mol Biol,2009,16(1):23-9.
[74]Papagiannakopoulos T, Friedmann-Morvinski D, Neveu P, et al. Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases.LID 10.1038/onc.2011.380 [doi]. Oncogene,2011.
[75]Adlakha YK, Saini N. MicroRNA-128 downregulates Bax and induces apoptosis in human embryonic kidneycells. Cell Mol Life Sci,2011,68(8):1415-28.
[76]Chen G, Zhu W, Shi D, et al. MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation bytargeting Bcl-2. Oncol Rep,2010,23(4):997-1003.
[77]Visone R, Veronese A, Rassenti LZ, et al. miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia. Blood,2011,118(11):3072-9.
[78]Iorio MV, Ferracin M, Liu CG, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res,2005,65(16):7065-70.
[79]Si ML, Zhu S, Wu H, et al. miR-21-mediated tumor growth. Oncogene,2007, 26(19):2799-803.
[80]Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res,2005,65(14):6029-33.
[81]Lee EJ, Gusev Y, Jiang J, et al. Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer,2007,120(5):1046-54.
[82]Roldo C, Missiaglia E, Hagan JP, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors areassociated with distinctive pathologic features and clinical behavior. J Clin Oncol,2006,24(29):4677-84.
[83]Meng F, Henson R, Lang M, et al. Involvement of human micro-RNA in growth and response to chemotherapy in humancholangiocarcinoma cell lines. Gastroenterology,2006,130(7):2113-29.
[84]Eis PS, Tam W, Sun L, et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A,2005, 102(10):3627-32.
[85]Kluiver J, Poppema S, de Jong D, et al. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J Pathol,2005, 207(2):243-9.
[86]Metzler M, Wilda M, Busch K, et al. High expression of precursor microRNA-155/BIC RNA in children with Burkittlymphoma. Genes Chromosomes Cancer,2004,39(2):167-9.
[87]Yanaihara N, Caplen N, Bowman E, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell,2006,9(3):189-98.
[88]Nikiforova MN, Tseng GC, Steward D, et al. MicroRNA expression profiling of thyroid tumors:biological significance anddiagnostic utility. J Clin Endocrinol Metab,2008,93(5):1600-8.
[89]Habbe N, Koorstra JB, Mendell JT, et al. MicroRNA miR-155 is a biomarker of early pancreatic neoplasia. Cancer Biol Ther,2009,8(4):340-6.
[90]Ryu JK, Hong SM, Karikari CA, et al. Aberrant MicroRNA-155 expression is an early event in the multistep progressionof pancreatic adenocarcinoma. Pancreatology,2010,10(1):66-73.
[91]Gronberg H, Damber L, Damber JE. Familial prostate cancer in Sweden.A nationwide register cohort study. Cancer,1996,77(1):138-43.
[92]Denis L, Morton MS, Griffiths K. Diet and its preventive role in prostatic disease. Eur Urol,1999,35(5-6):377-87.
[93]Fradet Y, Meyer F, Bairati I, et al. Dietary fat and prostate cancer progression and survival. Eur Urol,1999,35(5-6):388-91.
[94]Meyer F, Bairati I, Shadmani R, et al. Dietary fat and prostate cancer survival. Cancer Causes Control,1999,10(4):245-51.
[95]Bott SR. Management of recurrent disease after radical prostatectomy. Prostate Cancer Prostatic Dis,2004,7(3):211-6.
[96]Kindrick AV, Grossfeld GD, Stier DM, et al. Use of imaging tests for staging newly diagnosed prostate cancer:trends from theCaPSURE database. J Urol,1998, 160(6 Pt1):2102-6.
[97]Santos AF, Huang H, Tindall DJ. The androgen receptor:a potential target for therapy of prostate cancer. Steroids,2004,69(2):79-85.
[98]Porkka KP, Pfeiffer MJ, Waltering KK, et al. MicroRNA expression profiling in prostate cancer. Cancer Res,2007,67(13):6130-5.
[99]Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A,2006, 103(7):2257-61.
[100]Ozen M, Creighton CJ, Ozdemir M, et al. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene,2008, 27(12):1788-93.
[101]Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A,2008, 105(30):10513-8.
[102]Lodes MJ, Caraballo M, Suciu D, et al. Detection of cancer with serum miRNAs on an oligonucleotide microarray. PLoS One,2009,4(7):e6229.
[103]Lin SL, Chiang A, Chang D, et al. Loss of mir-146a function in hormone-refractory prostate cancer. RNA,2008,14(3):417-24.
[104]Musiyenko A, Bitko V, Barik S. Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells. J Mol Med (Berl),2008, 86(3):313-22.
[105]Gandellini P, Folini M, Longoni N, et al. miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res,2009,69(6):2287-95.
[106]Varambally S, Cao Q, Mani RS, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science,2008, 322(5908):1695-9.
[107]Raveche ES, Salerno E, Scaglione BJ, et al. Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood,2007, 109(12):5079-86.
[108]Linsley PS, Schelter J, Burchard J, et al. Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol Cell Biol, 2007,27(6):2240-52.
[109]Kong D, Li Y, Wang Z, et al. miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem Cells,2009,27(8):1712-21.
[110]Spahn M, Kneitz S, Scholz CJ, et al. Expression of microRNA-221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence. Int J Cancer,2010,127(2):394-403.
[111]Takeshita F, Patrawala L, Osaki M, et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther,2010,18(l):181-7.
[112]Sylvestre Y, De Guire V, Querido E, et al. An E2F/miR-20a autoregulatory feedback loop. J Biol Chem,2007,282(4):2135-43.
[113]Ambs S, Prueitt RL, Yi M, et al. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res, 2008,68(15):6162-70.
[114]Papagiannakopoulos T, Shapiro A, Kosik KS. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res,2008, 68(19):8164-72.
[115]Lu Z, Liu M, Stribinskis V, et al. MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene,2008,27(31):4373-9.
[116]Yang CH, Yue J, Fan M, et al. IFN induces miR-21 through a signal transducer and activator of transcription 3-dependent pathway as a suppressive negative feedback on IFN-induced apoptosis. Cancer Res,2010,70(20):8108-16.
[117]Parkin DM, Bray F, Ferlay J. Pisani P. Global cancer statistics,2002. CA Cancer J Clin,2005,55(2):74-108. [118]Siegel R, Ward E, Brawley O, et al. Cancer statistics,2011:the impact of eliminating socioeconomic and racialdisparities on premature cancer deaths. CA Cancer J Clin,2011,61(4):212-36.
[119]Stein JP, Quek ML, Skinner DG. Lymphadenectomy for invasive bladder cancer: Ⅰ. historical perspective andcontemporary rationale. BJU Int,2006,97(2):227-31.
[120]Liedberg F, Chebil G, Davidsson T, et al. Intraoperative sentinel node detection improves nodal staging in invasive bladdercancer. J Urol,2006,175(1):84-8; discussion 88-9.
[121]Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term resultsin 1,054 patients. J Clin Oncol,2001, 19(3):666-75.
[122]Shipley WU, Kaufman DS, Zehr E, et al. Selective bladder preservation by combined modality protocol treatment:long-termoutcomes of 190 patients with invasive bladder cancer. Urology,2002,60(1):62-7; discussion 67-8.
[123]Gottardo F, Liu CG, Ferracin M, et al. Micro-RNA profiling in kidney and bladder cancers. Urol Oncol,2007,25(5):387-92.
[124]Dyrskjot L, Ostenfeld MS, Bramsen JB, et al. Genomic profiling of microRNAs in bladder cancer:miR-129 is associated with poor outcome and promotes cell death in vitro. Cancer Res,2009,69(11):4851-60.
[125]Wang G, Chan ES, Kwan BC, et al. Expression of microRNAs in the Urine of Patients With Bladder Cancer. Clin Genitourin Cancer,2012.
[126]Han Y, Chen J, Zhao X, et al. MicroRNA expression signatures of bladder cancer revealed by deep sequencing. PLoS One,2011,6(3):e18286.
[127]夏伟,宋涛,李洁,等.临床膀肮癌组织中miRNA的差异表达研究.军事医学科学院院刊,2010,(06)：540-542.
[128]Yates DR, Rehman I, Abbod MF, et al. Promoter hypermethylation identifies progression risk in bladder cancer. Clin Cancer Res,2007,13(7):2046-53.
[129]Catto JW, Abbod MF, Wild PJ, et al. The application of artificial intelligence to microarray data:identification of a novel gene signature to identify bladder cancer progression. Eur Urol,2010,57(3):398-406.
[130]Veerla S, Lindgren D, Kvist A, et al. MiRNA expression in urothelial carcinomas: important roles of miR-10a, miR-222, miR-125b, miR-7 and miR-452 for tumor stage and metastasis, and frequent homozygous losses of miR-31. Int J Cancer, 2009,124(9):2236-42.
[131]Wiklund ED, Bramsen JB, Hulf T, et al. Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int J Cancer,2011, 128(6):1327-34.
[132]Neely LA, Rieger-Christ KM, Neto BS, et al.A microRNA expression ratio defining the invasive phenotype in bladder tumors. Urol Oncol,2010, 28(1):39-48.
[133]Catto JW, Miah S, Owen HC, et al. Distinct microRNA alterations characterize high- and low-grade bladder cancer. Cancer Res,2009,69(21):8472-81.
[134]Chiyomaru T, Enokida H, Tatarano S, et al. miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer. Br J Cancer,2010,102(5):883-91.
[135]Ichimi T, Enokida H, Okuno Y, et al. Identification of novel microRNA targets based on microRNA signatures in bladder cancer. Int J Cancer,2009, 125(2):345-52.
[136]Huang L, Luo J, Cai Q, et al. MicroRNA-125b suppresses the development of bladder cancer by targeting E2F3. Int J Cancer,2011,128(8):1758-69.
[137]夏伟,宋涛,李洁,等.Mir-200b抑制膀胱癌细胞T24的迁移.军事医学科学院院刊,2010,(05)：433-435.
[138]Lu Q, Lu C, Zhou GP, et al. MicroRNA-221 silencing predisposed human bladder cancer cells to undergo apoptosis induced by TRAIL. Urol Oncol,2010, 28(6):635-41.
[139]Dyrskjot L, Ostenfeld MS, Bramsen JB, et al. Genomic profiling of microRNAs in bladder cancer:miR-129 is associated with poor outcome and promotes cell death in vitro. Cancer Res,2009,69(11):4851-60.
[140]Villadsen SB, Bramsen JB, Ostenfeld MS, et al. The miR-143/-145 cluster regulates plasminogen activator inhibitor-1 in bladdercancer. Br J Cancer,2012, 106(2):366-74.
[141]Jemal A, Siegel R, Xu J, et al. Cancer statistics,2010. CA Cancer J Clin,2010, 60(5):277-300.
[142]Delahunt B, Eble JN, McCredie MR, et al. Morphologic typing of papillary renal cell carcinoma:comparison of growthkinetics and patient survival in 66 cases. Hum Pathol,2001,32(6):590-5.
[143]Redova M, Svoboda M, Slaby O. MicroRNAs and their target gene networks in renal cell carcinoma. Biochem Biophys Res Commun,2011,405(2):153-6.
[144]Dutta KK, Zhong Y, Liu YT, et al. Association of microRNA-34a overexpression with proliferation is cell type-dependent. Cancer Sci,2007,98(12):1845-52.
[145]Juan D, Alexe G, Antes T, et al. Identification of a microRNA panel for clear-cell kidney cancer. Urology,2010,75(4):835-41.
[146]Huang Y, Dai Y, Yang J, et al. Microarray analysis of microRNA expression in renal clear cell carcinoma. Eur J Surg Oncol,2009,35(10):1119-23.
[147]翟庆娜,周亮,余振东,等.大规模平行测序技术筛选人肾细胞癌组织中差异表达microRNAs及其验证.中国肿瘤生物治疗杂志,2011,(03)：306-310.
[148]White NM, Khella HW, Grigull J, et al. miRNA profiling in metastatic renal cell carcinoma reveals a tumour-suppressoreffect for miR-215. Br J Cancer,2011, 105(11):1741-9.
[149]冷慧敏,钱卫平,周亮,等.肾癌中MIR-184的异常表达及意义.北京大学学报(医学版),2011,(04)：509-513.
[150]Chow TF, Mankaruos M, Scorilas A, et al. The miR-17-92 cluster is over expressed in and has an oncogenic effect on renal cell carcinoma. J Urol,2010, 183(2):743-51.
[151]廖凯,洪艳,尹冰德,等.mir-27a、mir-200c及mir-145对肾癌细胞侵袭能力的影响.现代肿瘤医学,2011,(10)：1925-1929.
[152]Saini S, Yamamura S, Majid S, et al. MicroRNA-708 induces apoptosis and suppresses tumorigenicity in renal cancer cells. Cancer Res,2011, 71(19):6208-19.
[153]Zhang A, Liu Y, Shen Y, et al. miR-21 modulates cell apoptosis by targeting multiple genes in renal cell carcinoma. Urology,2011,78(2):474.e13-9.
[154]Li S, Chen T, Zhong Z, et al. microRNA-155 silencing inhibits proliferation and migration and induces apoptosisby upregulating BACH1 in renal cancer cells. Mol Med Report,2012,5(4):949-54.
[155]Nakada C, Matsuura K, Tsukamoto Y, et al. Genome-wide microRNA expression profiling in renal cell carcinoma:significant down-regulation of miR-141 and miR-200c. J Pathol,2008,216(4):418-27.
[156]Petillo D, Kort EJ, Anema J, et al. MicroRNA profiling of human kidney cancer subtypes. Int J Oncol,2009,35(1):109-14.
[157]Youssef YM, White NM, Grigull J, et al. Accurate molecular classification of kidney cancer subtypes using microRNAsignature. Eur Urol,2011,59(5):721-30.
[158]Gillis AJ, Stoop HJ, Hersmus R, et al. High-throughput microRNAome analysis in human germ cell tumours. J Pathol,2007,213(3):319-28.
[159]Looijenga LH, Gillis AJ, Stoop H, et al. Relevance of microRNAs in normal and malignant development, including human testicular germ cell tumours. Int J Androl,2007,30(4):304-14; discussion 314-5.
[160]Cheung HH, Davis AJ, Lee TL, et al. Methylation of an intronic region regulates miR-199a in testicular tumormalignancy. Oncogene,2011,30(31):3404-15.
[161]Lian J, Tian H, Liu L, et al. Downregulation of microRNA-383 is associated with male infertility and promotestesticular embryonal carcinoma cell proliferation by targeting IRF1. Cell Death Dis,2010,1:e94.
[162]Voorhoeve PM, le SC, Schrier M, et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testiculargerm cell tumors. Cell,2006, 124(6):1169-81.
[163]Chen ZH, Zhang GL, Li HR, et al. A panel of five circulating microRNAs as potential biomarkers for prostate cancer. LID-10.1002/pros.22495 [doi]. Prostate, 2012.
[164]Prueitt RL, Yi M, Hudson RS, et al. Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer. Prostate,2008,68(11):1152-64
[165]Takeshita F, Patrawala L, Osaki M, et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther,2010,18(1):181-7.
[166]Hanke M, Hoefig K, Merz H, et al. A robust methodology to study urine microRNA as tumor marker:microRNA-126 and microRNA-182 are related to urinary bladder cancer. Urol Oncol,2010,28(6):655-61.
[167]Yamada Y, Enokida H, Kojima S, et al. MiR-96 and miR-183 detection in urine serve as potential tumor markers of urothelial carcinoma:correlation with stage and grade, and comparison with urinary cytology. Cancer Sci,2011,102(3):522-9.
[168]Wszolek MF, Rieger-Christ KM, Kenney PA, et al.A MicroRNA expression profile defining the invasive bladder tumor phenotype. Urol Oncol, 2011,29(6):794-801.e1.
[169]Wulfken LM, Moritz R, Ohlmann C, et al. MicroRNAs in renal cell carcinoma: diagnostic implications of serum miR-1233 levels. PLoS One,2011,6(9):e25787.
[170]Powers MP, Alvarez K, Kim HJ, et al. Molecular classification of adult renal epithelial neoplasms using microRNA expression and virtual karyotyping. Diagn Mol Pathol,2011,20(2):63-70.
[171]Youssef YM, White NM, Grigull J, et al. Accurate molecular classification of kidney cancer subtypes using microRNA signature. Eur Urol,2011,59(5):721-30.
[2]Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer,2010.
[3]Siegel R, Ward E, Brawley O, et al. Cancer statistics,2011:the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin,2011,61(4):212-36.
[4]虞颂庭,臧美孚,夏溟,吴阶平.吴阶平泌尿外科学.济南：山东科学技术出版社,2004：919-942.
[5]张薇,刘振伟,阮志贤,等.1973-1999年上海市区老年人恶性肿瘤发病趋势分析.中华老年医学杂志,2005,(09)：701-704.
[6]魏矿荣,梁智恒,林茂合.中山市1970-1999年膀胱癌发病趋势分析.中国肿瘤,2005,(04)：235-237.
[7]Parkin DM.The global health burden of infection-associated cancers in the year 2002. Int J Cancer,2006,118(12):3030-44.
[8]Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst,1995, 87(7):524-30.
[9]Kaldor JM, Day NE, Kittelmann B, et al. Bladder tumours following chemotherapy and radiotherapy for ovarian cancer:a case-control study. Int J Cancer.1905,63(1):1-6.
[10]Liou SH, Lung JC, Chen YH, et al. Increased chromosome-type chromosome aberration frequencies as biomarkers of cancer risk in a blackfoot endemic area. Cancer Res,1999,59(7):1481-4.
[11]林辉,宋建勇,熊鸿燕.饮水氯消毒暴露与膀胱癌联系的病例对照研究.中国公共卫生,2002,(04)：22-24.
[12]Sturgeon SR, Hartge P, Silverman DT, et al. Associations between bladder cancer risk factors and tumor stage and grade at diagnosis. Epidemiology,1994, 5(2):218-25.
[13]Piper JM, Tonascia J, Matanoski GM. Heavy phenacetin use and bladder cancer in women aged 20 to 49 years. N Engl J Med,1985,313(5):292-5.
[14]Kiemeney LA, Schoenberg M. Familial transitional cell carcinoma. J Urol,1996, 156(3):867-72.
[15]Czene K, Lichtenstein P, Hemminki K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int J Cancer,2002,99(2):260-6.
[16]Lynch CF, Cohen MB. Urinary system.Cancer,1995,75(1 Suppl):316-29.
[17]Mungan NA, Aben KK, Schoenberg MP, et al. Gender differences in stage-adjusted bladder cancer survival. Urology,2000,55(6):876-80.
[18]El-Bolkainy MN, Mokhtar NM, Ghoneim MA, et al. The impact of schistosomiasis on the pathology of bladder carcinoma.Cancer,1981, 48(12):2643-8.
[19]Fleshner NE, Herr HW, Stewart AK, et al. The national cancer data base report on bladder carcinoma. The American college of surgeons Commission on Cancer and the American Cancer Society. Cancer,1996,78(7):1505-13.
[20]Kantor AF, Hartge P, Hoover RN, et al. Epidemiological characteristics of squamous cell carcinoma and adenocarcinoma of the bladder. Cancer Res, 1988,48(13):3853-5.
[21]Waters WB. Invasive bladder cancer-where do we go from here. J Urol,996, 155(6):1910-1.
[22]van RBW, Burger M, Lotan Y, et al. Recurrence and progression of disease in non-muscle-invasive bladder cancer:from epidemiology to treatment strategy. Eur Urol, 2009,56(3):430-42.
[23]Stein JP, Quek ML, Skinner DG. Lymphadenectomy for invasive bladder cancer: I. historical perspective and contemporary rationale. BJU Int,2006, 97(2):227-31.
[24]Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer:long-term results in 1,054 patients. J Clin Oncol,2001, 19(3):666-75.
[25]Kuczyk M, Turkeri L, Hammerer P, et al. Is there a role for bladder preserving strategies in the treatment of muscle-invasive bladder cancer. Eur Urol,2003, 44(1):57-64.
[26]Shipley WU, Kaufman DS, Zehr E, et al. Selective bladder preservation by combined modality protocol treatment:long-term outcomes of 190 patients with invasive bladder cancer. Urology,2002,60(1):62-7; discussion 67-8.
[27]Liedberg F, Chebil G, Davidsson T, et al. Intraoperative sentinel node detection improves nodal staging in invasive bladder cancer. J Urol,2006,175(1):84-8; discussion 88-9.
[28]Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell,1993, 75(5):843-54.
[29]Reinhart BJ, Slack FJ, Basson M, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature,2000,403(6772):901-6.
[30]Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A,2002,99(24):15524-9.
[31]Kutay H, Bai S, Datta J, et al. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem,2006,99(3):671-8.
[32]Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A,2006, 103(7):2257-61.
[33]Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature,2005,435(7043):834-8.
[34]Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A,2006, 103(7):2257-61.
[35]Gottardo F, Liu CG, Ferracin M, et al. Micro-RNA profiling in kidney and bladder cancers. Urol Oncol,2007,25(5):387-92
[36]Lim LP, Lau NC, Garrett-Engele P, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature.2005. 433(7027):769-73.
[37]Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet,2009,10(10):704-14.
[38]Shi XB, Xue L, Yang J, et al. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci U S A,2007,104(50):19983-8.
[39]Takamizawa J, Konishi H, Yanagisawa K, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res,2004,64(11):3753-6.
[40]Chow TF, Mankaruos M, Scorilas A, et al. The miR-17-92 cluster is over expressed in and has an oncogenic effect on renal cell carcinoma. J Urol,2010, 183(2):743-51.
[41]Chiyomaru T, Enokida H, Tatarano S, et al. miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer. Br J Cancer.2010,102(5):883-91.
[42]Mao ZG, He DS, Zhou J, et al. Differential expression of microRNAs in GH-secreting pituitary adenomas.Diagn Pathol,2010,5:79.
[43]林茂松.人结直肠癌microRNA表达谱及其临床意义的研究：苏州大学,2010.
[44]Meiri E, Levy A, Benjamin H, et al. Discovery of microRNAs and other small RNAs in solid tumors. Nucleic Acids Res,2010,38(18):6234-46.
[45]Griffiths-Jones S. miRBase:microRNA sequences and annotation. Curr Protoc Bioinformatics,2010, Chapter 12:Unit 12.9.1-10.
[46]Pollack A, Wu CS, Czerniak B, et al. Abnormal bcl-2 and pRb expression are independent correlates of radiationresponse in muscle-invasive bladder cancer. Clin Cancer Res,1997,3(10):1823-9.
[47]Lipponen PK. Expression of c-myc protein is related to cell proliferation and expression ofgrowth factor receptors in transitional cell bladder cancer. J Pathol, 1995,175(2):203-10.
[48]Montie JE. CDC91L1 (PIG-U) is a newly discovered oncogene in human bladder cancer. J Urol,2005,174(3):869-70.
[49]van RBW, Lurkin I, Radvanyi F, et al. The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator ofsuperficial bladder cancer with low recurrence rate. Cancer Res,2001,61(4):1265-8.
[50]柳建军,苏劲.P53.C-erbB-2和bcl-2基因在膀胱癌中的表达及意义.临床泌尿外科杂志,2001,(08)：368-370.
[51]李和程,王子明.P53和MDM2基因表达及与膀胱癌生物学行为的关系.临床泌尿外科杂志,2001,(12)：526-528.
[52]Calin GA, Sevignani C, Dumitru CD, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A,2004,101(9):2999-3004.
[53]Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature,2005,435(7043):834-8.
[54]Huang Y, Dai Y, Yang J, et al. Microarray analysis of microRNA expression in renal clear cell carcinoma. Eur J Surg Oncol,2009,35(10):1119-23.
[55]Dyrskjot L, Ostenfeld MS, Bramsen JB, et al. Genomic profiling of microRNAs in bladder cancer:miR-129 is associated with pooroutcome and promotes cell death in vitro. Cancer Res,2009,69(11):4851-60.
[56]Yanaihara N, Caplen N, Bowman E, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell,2006,9(3):189-98.
[57]Liu CJ, Kao SY, Tu HF, et al. Increase of microRNA miR-31 level in plasma could be a potential marker of oralcancer. Oral Dis,2010,16(4):360-4.
[58]Hanke M, Hoefig K, Merz H, et al. A robust methodology to study urine microRNA as tumor marker:microRNA-126 andmicroRNA-182 are related to urinary bladder cancer. Urol Oncol,2010,28(6):655-61.
[59]Ng EK, Chong WW, Jin H, et al. Differential expression of microRNAs in plasma of patients with colorectalcancer:a potential marker for colorectal cancer screening. Gut,2009,58(10):1375-81.
[60]Catto JW, Abbod MF, Wild PJ, et al.The application of artificial intelligence to microarray data:identification of a novel gene signature to identify bladder cancer progression. Eur Urol,2010,57(3):398-406.
[61]Veerla S, Lindgren D, Kvist A, et al. MiRNA expression in urothelial carcinomas: important roles of miR-10a, miR-222,miR-125b, miR-7 and miR-452 for tumor stage and metastasis, and frequenthomozygous losses of miR-31. Int J Cancer, 2009,124(9):2236-42.
[62]Gregory RI, Shiekhattar R. MicroRNA biogenesis and cancer. Cancer Res,2005, 65(9):3509-12.
[63]Sevignani C, Calin GA, Siracusa LD, et al. Mammalian microRNAs:a small world for fine-tuning gene expression. Mamm Genome,2006,17(3):189-202.
[64]Miranda KC, Huynh T, Tay Y, et al. A pattern-based method for the identification of MicroRNA binding sites and theircorresponding heteroduplexes.Cell,2006, 126(6):1203-17.
[65]Saetrom O, Snove O Jr, Saetrom P. Weighted sequence motifs as an improved seeding step in microRNA targetprediction algorithms. RNA,2005, 11(7):995-1003.
[66]Saetrom P, Snove O Jr. Robust machine learning algorithms predict microRNA genes and targets. Methods Enzymol,2007,427:25-49.
[67]Ozen M, Creighton CJ, Ozdemir M, et al. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene,2008,27(12):1788-93.
[68]Markou A, Tsaroucha EG, Kaklamanis L, et al. Prognostic value of mature microRNA-21 and microRNA-205 overexpression innon-small cell lung cancer by quantitative real-time RT-PCR. Clin Chem,2008,54(10):1696-704.
[69]Zhu S, Si ML, Wu H, et al. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem,2007.282(19):14328-36.
[70]Tsang WP, Kwok TT. Epigallocatechin gallate up-regulation of miR-16 and induction of apoptosis inhuman cancer cells.J Nutr Biochem,2010,21(2):140-6.
[71]Kaddar T, Rouault JP, Chien WW, et al. Two new miR-16 targets:caprin-1 and HMGA1, proteins implicated in cellproliferation. Biol Cell,2009,101(9):511-24.
[72]Levin WJ, Press MF, Gaynor RB, et al. Expression patterns of immediate early transcription factors in human non-smallcell lung cancer. The lung cancer study group. Oncogene,1995,11(7):1261-9.
[73]Dunand-Sauthier I, Santiago-Raber ML, Capponi L, et al. Silencing of c-Fos expression by microRNA-155 is critical for dendritic cellmaturation and function. Blood,2011,117(17):4490-500.
[74]Lee HJ, Palkovits M,3rd YWS. miR-7b, a microRNA up-regulated in the hypothalamus after chronic hyperosmolarstimulation, inhibits Fos translation. Proc Natl Acad Sci U S A,2006,103(42):15669-74.
[75]Malaguarnera R, Vella V, Vigneri R, et al. p53 family proteins in thyroid cancer. Endocr Relat Cancer,2007,14(1):43-60.
[76]Yamasaki L. Role of the RB tumor suppressor in cancer. Cancer Treat Res,2003, 115:209-39.
[77]Liu J, Stevens J, Rote CA, et al. Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to theadenomatous polyposis coli protein. Mol Cell,2001, 7(5):927-36.
[78]Le MT, Teh C, Shyh-Chang N, et al. MicroRNA-125b is a novel negative regulator of p53. Genes Dev,2009,23(7):862-76.
[79]Cai K, Wang Y, Bao X. MiR-106b promotes cell proliferation via targeting RB in laryngeal carcinoma. J Exp Clin Cancer Res,2011,30:73.
[80]Liang C, Feng P, Ku B, et al. Autophagic and tumour suppressor activity of a novel Beclinl-binding proteinUVRAG Nat Cell Biol,2006,8(7):688-99.
[81]Lorsbach RB, Moore J, Mathew S, et al. TET1, a member of a novel protein family, is fused to MLL in acute myeloidieukemia containing the t(10;11)(q22;q23). Leukemia,2003,17(3):637-41.
[82]Ono R, Taki T, Taketani T, et al. LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acutemyeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). Cancer Res,2002,62(14):4075-80.
[83]Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLLpartner TET1. Science, 2009,324(5929):930-5.
[84]Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryoniclethality. Cell,1992,69(6):915-26.
[85]Dahl C, Gronbaek K, Guldberg P. Advances in DNA methylation: 5-hydroxymethylcytosine revisited. Clin Chim Acta,2011,412(11-12):831-6.
[86]Johnson SM, Grosshans H, Shingara J, et al. RAS is regulated by the let-7 microRNA family. Cell,2005,120(5):635-47.
[87]Akao Y, Nakagawa Y, Naoe T. let-7 microRNA functions as a potential growth suppressor in human colon cancercells. Biol Pharm Bull,2006,29(5):903-6.
[88]Takamizawa J, Konishi H, Yanagisawa K, et al. Reduced expression of the let-7 microRNAs in human lung cancers in associationwith shortened postoperative survival. Cancer Res,2004,64(11):3753-6.
[89]Jerome T, Laurie P, Louis B, et al. Enjoy the Silence:The Story of let-7 MicroRNA and Cancer. Curr Genomics,2007,8(4):229-33.
[90]Mayr C, Hemann MT, Bartel DP. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science,2007,315(5818):1576-9.
[91]Lee YS, Dutta A. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev,2007,21 (9):1025-30.
[92]Klemke M, Meyer A, Hashemi NM, et al. Loss of let-7 binding sites resulting from truncations of the 3'untranslatedregion of HMGA2 mRNA in uterine leiomyomas. Cancer Genet Cytogenet,2010,196(2):119-23.
[93]Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify buman cancers. Nature,2005,435(7043):834-8.
[94]Kawasaki H, Taira K. MicroRNA-196 inhibits HOXB8 expression in myeloid differentiation of HL60 cells. Nucleic Acids Symp Ser (Oxf),2004,(48):211-2.
[95]Eulalio A, Huntzinger E, Nishihara T, et al. Deadenylation is a widespread effect of miRNA regulation. RNA,2009,15(1):21-32.
[96]He L, Hannon GJ. MicroRNAs:small RNAs with a big role in gene regulation. Nat Rev Genet,2004,5(7):522-31.
[97]Kim VN. Small RNAs:classification, biogenesis, and function. Mol Cells,2005, 19(1):1-15.
[98]Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol,2009,4:199-227.
[99]Schmittgen TD. miR-31:a master regulator of metastasis. Future Oncol, 2010,6(1):17-20.
[100]Segura MF, Hanniford D, Menendez S, et al. Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proc Natl Acad Sci U S A,2009, 106(6):1814-9.
[101]Sotiropoulou G, Pampalakis G, Lianidou E, et al. Emerging roles of microRNAs as molecular switches in the integrated circuit ofthe cancer cell. RNA,2009, 15(8):1443-61.
[102]Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol,2009,4:199-227.
[103]Wong CM, Wong CC, Lee JM, et al. Sequential alterations of miRNA expression in hepatocellular carcinoma development and venous metastasis. LID-10.1002/hep.25512 [doi]. Hepatology,2011.
[104]Donnem T, Fenton CG, Lonvik K, et al. MicroRNA signatures in tumor tissue related to angiogenesis in non-small celllung cancer. PLoS One,2012, 7(1):e29671.
[105]Bovell L, Shanmugam C, Katkoori VR, et al. miRNAs are stable in colorectal cancer archival tissue blocks. Front Biosci (Elite Ed),2012,4:1937-40.
[106]Alshatwi AA, Shafi G, Hasan TN, et al. Differential Expression Profile and Genetic Variants of MicroRNAs Sequences inBreast Cancer Patients. PLoS One, 2012,7(2):e30049.
[107]Chen ZH, Zhang GL, Li HR, et al. A panel of five circulating microRNAs as potential biomarkers for prostatecancer.LID-10.1002/pros.22495 [doi]. Prostate, 2012.
[108]Costa FF, Bischof JM, Vanin EF, et al. Identification of microRNAs as potential prognostic markers in ependymoma. PLoS One,2011,6(10):e25114.
[109]Schmeier S, Schaefer U, Essack M, et al. Network analysis of microRNAs and their regulation in human ovarian cancer. BMC Syst Biol,2011,5:183.
[110]de Oliveira JC, Scrideli CA, Brassesco MS, et al. Differential miRNA expression in childhood acute lymphoblastic leukemia andassociation with clinical and biological features. Leuk Res,2012,36(3):293-8.
[111]Wang G, Chan ES, Kwan BC, et al. Expression of microRNAs in the urine of patients with bladder cancer. Clin Genitourin Cancer,2012.
[112]Song T, Xia W, Shao N, et al. Differential miRNA expression profiles in bladder urothelial carcinomas. Asian Pac J Cancer Prev,2010, 11(4):905-11.
[113]Xie P, Xu F, Cheng W, et al. Detection, verification and significance of differentially expressed miRNAs inbladder urothelial carcinoma. Zhonghua Yi Xue Za Zhi,2010,90(48):3391-4.
[114]Tuck AB, Park M, Sterns EE, et al. Coexpression of hepatocyte growth factor and receptor (Met) in human breastcarcinoma. Am J Pathol,1996, 148(1):225-32.
[115]Eis PS, Tam W, Sun L, et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A,2005,102(10):3627-32.
[116]Iorio MV, Ferracin M, Liu CG, et al. Micro RNA gene expression deregulation in human breast cancer. Cancer Res,2005,65(16):7065-70.
[117]Buechner J, Tomte E, Haug BH, et al. Tumour-suppressor microRNAs let-7 and mir-101 target the proto-oncogene MYCN and inhibit cell proliferation in MYCN-amplified neuroblastoma. Br J Cancer,2011,105(2):296-303.
[118]Wang V, Wu W. MicroRNA-based therapeutics for cancer. BioDrugs,2009, 23(1):15-23.
[119]Takeshita F, Patrawala L, Osaki M, et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther.2010,18(1):181-7.
[120]Braun J, Hoang-Vu C, Dralle H, et al. Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas. Oncogene, 2010,29(29):4237-44.
[121]Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition bytargeting ZEB1 and SIP1. Nat Cell Biol,2008,10(5):593-601.
[122]Park SM, Gaur AB, Lengyel E, et al. The miR-200 family determines the epithelial phenotype of cancer cells bytargeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev,2008,22(7):894-907.
[123]Nan Y, Han L, Zhang A, et al. MiRNA-451 plays a role as tumor suppressor in human glioma cells. Brain Res,2010,1359:14-21.
[124]Godlewski J, Nowicki MO, Bronisz A, et al. MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolicstress in glioma cells. Mol Cell,2010,37(5):620-32.
[125]Zhu S, Wu H, Wu F, et al. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res,2008,18(3):350-9.
[126]Bhaumik D, Scott GK, Schokrpur S, et al. Expression of microRNA-146 suppresses NF-kappaB activity with reduction ofmetastatic potential in breast cancer cells. Oncogene,2008,27(42):5643-7.
[127]Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature,2007,449(7163):682-8.
[128]Galardi S, Mercatelli N, Giorda E, et al. miR-221 and miR-222 expression affects the proliferation potential of humanprostate carcinoma cell lines by targeting p27Kipl. J Biol Chem,2007,282(32):23716-24.
[129]Liu Y, Wang HX, Lu N, et al. Translocation of annexin I from cellular membrane to the nuclear membrane inhuman esophageal squamous cell carcinoma. World J Gastroenterol,2003,9(4):645-9.
[130]Duncan R, Carpenter B, Main LC, et al. Characterisation and protein expression profiling of annexins in colorectaicancer. Br J Cancer,2008,98(2):426-33.
[131]Bai XF, Ni XG, Zhao P, et al. Overexpression of annexin 1 in pancreatic cancer and its clinical significance. World J Gastroenterol,2004,10(10):1466-70.
[132]Yang LP, Yang ZL, Tan XG, et al. Expression of annexin A1 (ANXA1) and A2 (ANXA2) and its significance in benignand malignant lesions of gallbladder. Zhonghua Zhong Liu Za Zhi,2010,32(8):595-9.
[133]Luthra R, Singh RR, Luthra MG, et al. MicroRNA-196a targets annexin A1:a microRNA-mediated mechanism of annexin A1downregulation in cancers. Oncogene,2008,27(52):6667-78.
[134]Si ML, Zhu S, Wu H, et al. miR-21-mediated tumor growth. Oncogene,2007, 26(19):2799-803.
[135]Kim S, Lee UJ, Kim MN, et al. MicroRNA miR-199a* regulates the MET proto-oncogene and the downstreamextracellular signal-regulated kinase 2 (ERK2). J Biol Chem,2008,283(26):18158-66.
[136]Johnson SM, Grosshans H, Shingara J, et al. RAS is regulated by the let-7 microRNA family. Cell,2005,120(5):635-47.
[137]Matsubara H, Takeuchi T, Nishikawa E, et al. Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20ain lung cancers overexpressing miR-17-92. Oncogene,2007,26(41):6099-105.
[138]Kondo N, Toyama T, Sugiura H, et al. miR-206 Expression is down-regulated in estrogen receptor alpha-positive humanbreast cancer. Cancer Res,2008, 68(13):5004-8.
[139]Meng F, Henson R, Wehbe-Janek H, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in humanhepatocellular cancer. Gastroenterology,2007,133(2):647-58.
[140]Fischer U, Janicke RU, Schulze-Osthoff K. Many cuts to ruin:a comprehensive update of caspase substrates. Cell Death Differ,2003,10(1):76-100.
[141]Dasmahapatra G, Almenara JA, Grant S. Flavopiridol and histone deacetylase inhibitors promote mitochondrial injury and cell death in human leukemia cells that overexpress Bcl-2. Mol Pharmacol,2006,69(1):288-98.
[142]Youssef AM, Malki A, Badr MH, et al. Synthesis and Anticancer Activity of Novel Benzimidazole and BenzothiazoleDerivatives against HepG2 Liver Cancer Cells. Med Chem,2012.
[143]Sato M, Tsujino I, Fukunaga M, et al. Cyclosporine A induces apoptosis of human lung adenocarcinoma cells viacaspase-dependent pathway. Anticancer Res,2011,31(6):2129-34.
[144]Wang J, Li Q, Ou Y, et al. Inhibition of tumor growth by recombinant adenovirus containing human lactoferrinthrough inducing tumor cell apoptosis in mice bearing EMT6 breast cancer. Arch Pharm Res,2011,34(6):987-95.
[145]Park C, Jin CY, Kim GY, et al. Induction of apoptosis by ethanol extract of Prunus mume in U937 human leukemiacells through activation of caspases. Oncol Rep,2011,26(4):987-93.
[146]Mishunina TM, Kalinichenko OV, Tronko MD, et al. Caspase-3 activity in papillary thyroid carcinomas. Exp Oncol,2010,32(4):269-72.
[147]Joo SS, Yoo YM. Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways:therapeutic implications for prostate cancer. J Pineal Res, 2009,47(1):8-14.
[148]Shen L, Zeng S, Chen J, et al. El A inhibits the proliferation of human cervical cancer cells (HeLa cells) byapoptosis induction through activation of HER-2/Neu/Caspase-3 pathway. Med Oncol,2008,25(2):222-8.
[149]Fang YX, Xue JL, Shen Q, et al. miR-7 inhibits tumor growth and metastasis by targeting the PI3K/AKT pathway inhepatocellular carcinoma.LID 10.1002/hep.25576 [doi]. Hepatology,2012.
[150]Ohdaira H, Sekiguchi M, Miyata K, et al. MicroRNA-494 suppresses cell proliferation and induces senescence in A549 lungcancer cells. Cell Prolif,2012, 45(1):32-8.
[151]Cai C, Ashktorab H, Pang X, et al. MicroRNA-211 expression promotes colorectal cancer cell growth in vitro and invivo by targeting tumor suppressor CHD5. PLoS One,2012,7(1):e29750.
[152]Akhavantabasi S, Sapmaz A, Tuna S, et al. miR-125b Targets ARID3B in Breast Cancer Cells. Cell Struct Funct,2012,37(1):27-38.
[153]Kojima S, Chiyomaru T, Kawakami K, et al. Tumour suppressors miR-1 and miR-133a target the oncogenic function of purinenucleoside phosphorylase (PNP) in prostate cancer. Br J Cancer,2012,106(2):405-13.
[154]Kovaleva V, Mora R, Park YJ, et al. MicroRNA-130a targets ATG2B and DICER1 to inhibit autophagy and trigger killingof chronic lymphocytic leukemia cells. Cancer Res,2012.
[155]O'Connor L, Strasser A, O'Reilly LA, et al. Bim:a novel member of the Bcl-2 family that promotes apoptosis. EMBO J,1998,17(2):384-95.
[156]Liu JW, Chandra D, Tang SH, et al. Identification and characterization of Bimgamma, a novel proapoptotic BH3-onlysplice variant of Bim. Cancer Res, 2002,62(10):2976-81.
[157]Sunters A, de Mattos S F, Stahl M, et al. FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treatedbreast cancer cell lines. J Biol Chem, 2003,278(50):49795-805.
[158]Zhang H, Zuo Z, Lu X, et al. MiR-25 regulates apoptosis by targeting Bim in human ovarian cancer. Oncol Rep,2012,27(2):594-8.
[159]Tatarano S, Chiyomaru T, Kawakami K, et al. Novel oncogenic function of mesoderm development candidate 1 and its regulationby MiR-574-3p in bladder cancer cell lines. Int J Oncol,2012,40(4):951-9.
[160]Yoshino H, Enokida H, Chiyomaru T, et al. Tumor suppressive microRNA-1 mediated novel apoptosis pathways through directinhibition of splicing factor serine/arginine-rich 9 (SRSF9/SRp30c) in bladdercancer. Biochem Biophys Res Commun,2012,417(1):588-93.
[161]Hirata H, Hinoda Y, Ueno K, et al. MicroRNA-1826 targets VEGFC, beta-catenin (CTNNB1) and MEK1 (MAP2K1) in humanbladder cancer. Carcinogenesis,2012,33(1):41-8.
[162]Ming J, Jiang G, Zhang Q, et al. Interleukin-7 up-regulates cyclin D1 via activator protein-1 to promoteproliferation of cell in lung cancer. Cancer Immunol Immunother,2012,61(1):79-88.
[163]Mahner S, Baasch C, Schwarz J, et al. C-Fos expression is a molecular predictor of progression and survival inepithelial ovarian carcinoma. Br J Cancer,2008, 99(8):1269-75.
[164]Lin YF, Wu MS, Chang CC, et al. Comparative immunoproteomics of identification and characterization of virulence factors from Helicobacter pylori related to gastric cancer. Mol Cell Proteomics,2006,5(8):1484-96.
[165]Vairaktaris E, Papakosta V, Derka S, et_al. H-ras and c-Fos exhibit similar expression patterns during most stages of oraloncogenesis. In Vivo,2008, 22(5):621-8.
[166]Baan B, Pardali E, ten DP, et al. In situ proximity ligation detection of c-Jun/AP-1 dimers reveals increasedlevels of c-Jun/Fral complexes in aggressive breast cancer cell lines in vitroand in vivo. Mol Cell Proteomics, 2010,9(9):1982-90.
[167]Yao HQ, Peng Y, Zhong ZZ, et al. Association of the expressions of platelet-derived growth factor receptor andc-Fos with the biological characteristics of bladder cancer. Di Yi Jun Yi Da Xue Xue Bao,2004, 24(2):177-9.
[168]Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer,2007,7(12):961-7.
[169]Maiuri MC, Tasdemir E, Criollo A, et al. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ,2009,16(1):87-93.
[170]Wu T, Li Y, Gong L, et al. Multi-step process of human breast carcinogenesis:a role for BRCA1, BECN1,CCND1, PTEN and UVRAG Mol Med Report, 2012,5(2):305-12.
[171]Thoresen SB, Pedersen NM, Liestol K, et al. A phosphatidylinositol 3-kinase class III sub-complex containing VPS 15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytictraffic. Exp Cell Res,2010, 316(20):3368-78.
[172]Takahashi Y, Coppola D, Matsushita N, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy andtumorigenesis. Nat Cell Biol, 2007,9(10):1142-51.
[173]Liang C, Feng P, Ku B, et al. UVRAG:a new player in autophagy and tumor cell growth. Autophagy,2007,3(1):69-71.
[174]Liang C, Lee JS, Inn KS, et al. Beclinl-binding UVRAG targets the class C Vps complex to coordinate autophagosomematuration and endocytic trafficking. Nat Cell Biol,2008,10(7):776-87.
[1]Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell,1993, 75(5):843-54.
[2]Reinhart BJ, Slack FJ, Basson M, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature,2000,403(6772):901-6.
[3]Lagos-Quintana M, Rauhut R, Lendeckel W, et al. Identification of novel genes coding for small expressed RNAs. Science,2001,294(5543):853-8.
[4]Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science,2001,294(5543):862-4.
[5]Ruvkun G. Molecular biology. Glimpses of a tiny RNA world. Science,2001, 294(5543):797-9.
[6]Lau NC, Lim LP, Weinstein EG, et al. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science,2001, 294(5543):858-62.
[7]Voinnet O. Origin, biogenesis, and activity of plant rnicroRNAs. Cell,2009, 136(4):669-87.
[8]Xiao C, Rajewsky K. MicroRNA control in the immune system:basic principles. Cell,2009,136(1):26-36.
[9]Chendrimada TP, Gregory RI, Kumaraswamy E, et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature,2005, 436(7051):740-4.
[10]Lee Y, Hur I, Park SY, et al. The role of PACT in the RNA silencing pathway.EMBO J,2006,25(3):522-32.
[11]Schaefer A, Jung M, Kristiansen G, et al. MicroRNAs and cancer:current state and future perspectives in urologic oncology. Urol Oncol,2010,28(1):4-13.
[12]Ruvkun G. Molecular biology. Glimpses of a tiny RNA world. Science,2001, 294(5543):797-9.
[13]Lau NC, Lim LP, Weinstein EG, et al. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science,2001, 294(5543):858-62.
[14]McDonald JS, Milosevic D, Reddi HV, et al. Analysis of circulating microRNA: preanalytical and analytical challenges. Clin Chem,2011,57(6):833-40.
[15]Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One,2008,3(9):e3148.
[16]Pasquinelli AE, Reinhart BJ, Slack F, et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature,2000, 408(6808):86-9.
[17]Lau NC, Lim LP, Weinstein EG, et al. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science,2001, 294(5543):858-62.
[18]Reinhart BJ, Weinstein EG, Rhoades MW, et al. MicroRNAs in plants. Genes Dev, 2002,16(13):1616-26.
[19]Chen CZ, Li L, Lodish HF, et al. MicroRNAs modulate hematopoietic lineage differentiation. Science,2004,303(5654):83-6.
[20]Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science,2001,294(5543):862-4.
[21]Lagos-Quintana M, Rauhut R, Lendeckel W, et al. Identification of novel genes coding for small expressed RNAs. Science,2001,294(5543):853-8.
[22]Johnson CD, Esquela-Kerscher A, Stefani G, et al. The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res,2007,67(16):7713-22.
[23]Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet,2009,10(10):704-14.
[24]Lim LP, Lau NC, Garrett-Engele P, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature,2005, 433(7027):769-73.
[25]Song JJ, Smith SK, Hannon GJ, et al. Crystal structure of Argonaute and its implications for RISC slicer activity. Science,2004,305(5689):1434-7.
[26]Liu J, Carmell MA, Rivas FV, et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science,2004,305(5689):1437-41.
[27]Wu L, Fan J, Belasco JG MicroRNAs direct rapid deadenylation of mRNA. Proc Natl Acad Sci U S A,2006,103(11):4034-9.
[28]Orom UA, Nielsen FC, Lund AH. MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell,2008,30(4):460-71.
[29]Flynt AS, Lai EC. Biological principles of microRNA-mediated regulation: shared themes amiddiversity. Nat Rev Genet,2008,9(11):831-42.
[30]Lim LP, Lau NC, Weinstein EG, et al.The microRNAs of Caenorhabditis elegans. Genes Dev,2003,17(8):991-1008.
[31]Sempere LF, Freemantle S, Pitha-Rowe I, et al. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol,2004, 5(3):R13.
[32]Castoldi M, Schmidt S, Benes V. et al. miChip:an array-based method for microRNA expression profiling using lockednucleic acid capture probes. Nat Protoc,2008,3(2):321-9.
[33]Chen C, Ridzon DA, Broomer AJ, et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res.2005,33(20):e179.
[34]Raymond CK, Roberts BS, Garrett-Engele P, et al. Simple, quantitative primer-extension PCR assay for direct monitoring ofmicroRNAs and short-interfering RNAs. RNA,2005,11 (11):1737-44.
[35]Zhang W, Dahlberg JE, Tam W. MicroRNAs in tumorigenesis:a primer. Am J Pathol,2007,171(3):728-38.
[36]Grundhoff A, Sullivan CS, Ganem D. A combined computational and microarray-based approach identifies novel microRNAsencoded by human gamma-herpesviruses. RNA,2006,12(5):733-50.
[37]Castoldi M, Schmidt S, Benes V, et al. miChip:an array-based method for microRNA expression profiling using lockednucleic acid capture probes. Nat Protoc,2008,3(2):321-9.
[38]Beuvink I, Kolb FA, Budach W, et al. A novel microarray approach reveals new tissue-specific signatures of known andpredicted mammalian microRNAs. Nucleic Acids Res,2007,35(7):e52.
[39]Hua YJ, Tu K, Tang ZY, et al. Comparison of normalization methods with microRNA microarray. Genomics,2008,92(2):122-8.
[40]Castoldi M, Schmidt S, Benes V, et al. A sensitive array for microRNA expression profiling (miChip) based on lockednucleic acids (LNA). RNA,2006, 12(5):913-20.
[41]Lagos-Quintana M, Rauhut R, Yalcin A, et al. Identification of tissue-specific microRNAs from mouse. Curr Biol,2002,12(9):735-9.
[42]'t HPA, Ariyurek Y, Thygesen HH, et al. Deep sequencing-based expression analysis shows major advances in robustness, resolution and inter-lab portability over five microarray platforms. Nucleic Acids Res,2008,36(21):e141.
[43]Szittya G, Moxon S, Santos DM, et al. High-throughput sequencing of Medicago truncatula short RNAs identifies eight newmiRNA families. BMC Genomics, 2008,9:593.
[44]Rathjen T, Pais H, Sweetman D, et al. High throughput sequencing of microRNAs in chicken somites. FEBS Lett,2009,583(9):1422-6.
[45]Glazov EA, Cottee PA, Barris WC, et al.A microRNA catalog of the developing chicken embryo identified by a deepsequencing approach. Genome Res,2008, 18(6):957-64.
[46]Chellappan P, Jin H. Discovery of plant microRNAs and short-interfering RNAs by deep parallelsequencing. Methods Mol Biol,2009,495:121-32.
[47]Morozova O, Marra MA. Applications of next-generation sequencing technologies in functional genomics. Genomics,2008,92(5):255-64.
[48]Wyman SK, Parkin RK, Mitchell PS, et al. Repertoire of microRNAs in epithelial ovarian cancer as determined by nextgeneration sequencing of small RNA cDNA libraries. PLoS One,2009,4(4):e5311.
[49]Hafner M, Landgraf P, Ludwig J, et al. Identification of microRNAs and other small regulatory RNAs using cDNA librarysequencing. Methods,2008, 44(1):3-12.
[50]Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A,2002,99(24):15524-9.
[51]Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A,2005,102(39):13944-9.
[52]Kutay H, Bai S, Datta J, et al. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem,2006,99(3):671-8.
[53]Roldo C, Missiaglia E, Hagan JP, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol,2006,24(29):4677-84.
[54]Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets, Proc Natl Acad Sci U S A,2006, 103(7):2257-61.
[55]Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature,2005,435(7043):834-8.
[56]Calin GA, Croce CM, MicroRNA signatures in human cancers. Nat Rev Cancer, 2006,6(11):857-66.
[57]Zhang B, Pan X, Cobb GP, et al. microRNAs as oncogenes and tumor suppressors. Dev Biol,2007,302(1):1-12.
[58]Esquela-Kerscher A, Slack FJ. Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer,2006,6(4):259-69.
[59]Hua S, Xiaotao X, Renhua G, et al. Reduced miR-31 and let-7 maintain the balance between differentiation andquiescence in lung cancer stem-like side population cells. Biomed Pharmacother,2012.
[60]Shimizu S, Takehara T, Hikita H, et al. The let-7 family of microRNAs inhibits Bcl-xL expression and potentiatessorafenib-induced apoptosis in human hepatocellular carcinoma. J Hepatol,2010,52(5):698-704.
[61]O'Day E, Lal A. MicroRNAs and their target gene networks in breast cancer. Breast Cancer Res,2010,12(2):201.
[62]Nishino J, Kim I, Chada K, et al. Hmga2 promotes neural stem cell self-renewal in young but not old mice byreducing p16Ink4a and p19Arf Expression. Cell, 2008,135(2):227-39.
[63]Yu F, Yao H, Zhu P, et al. let-7 regulates self-renewal and tumorigenicity of breast cancer cells. Cell,2007,131(6):1109-23.
[64]Takamizawa J, Konishi H, Yanagisawa K, et al. Reduced expression of the let-7 microRNAs in human lung cancers in associationwith shortened postoperative survival. Cancer Res,2004,64(11):3753-6.
[65]Fang WJ, Lin CZ, Zhang HH, et al. Detection of let-7a microRNA by real-time PCR in colorectal cancer:asingle-centre experience from China. J Int Med Res, 2007,35(5):716-23.
[66]Lee YS, Dutta A. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev,2007,21(9):1025-30.
[67]Liu Q, Lv GD, Qin X, et al. Role of microRNA let-7 and effect to HMGA2 in esophageal squamous cell carcinoma. Mol Biol Rep,2012,39(2):1239-46.
[68]Sampson VB, Rong NH, Han J, et al. MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkittlymphoma cells. Cancer Res,2007, 67(20):9762-70.
[69]Kumar MS, Lu J, Mercer KL, et al. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet,2007,39(5):673-7.
[70]Johnson SM, Grosshans H, Shingara J, et al. RAS is regulated by the let-7 microRNA family. Cell,2005,120(5):635-47.
[71]He XY, Chen JX, Zhang Z, et al. The let-7a microRNA protects from growth of lung carcinoma by suppression ofk-Ras and c-Myc in nude mice. J Cancer Res Clin Oncol,2010,136(7):1023-8.
[72]Garzon R, Calin GA, Croce CM. MicroRNAs in Cancer. Annu Rev Med,2009, 60:167-79.
[73]Park SY, Lee JH, Ha M, et al. miR-29 miRNAs activate p53 by targeting p85 alpha and CDC42. Nat Struct Mol Biol,2009,16(1):23-9.
[74]Papagiannakopoulos T, Friedmann-Morvinski D, Neveu P, et al. Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases.LID 10.1038/onc.2011.380 [doi]. Oncogene,2011.
[75]Adlakha YK, Saini N. MicroRNA-128 downregulates Bax and induces apoptosis in human embryonic kidneycells. Cell Mol Life Sci,2011,68(8):1415-28.
[76]Chen G, Zhu W, Shi D, et al. MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation bytargeting Bcl-2. Oncol Rep,2010,23(4):997-1003.
[77]Visone R, Veronese A, Rassenti LZ, et al. miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia. Blood,2011,118(11):3072-9.
[78]Iorio MV, Ferracin M, Liu CG, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res,2005,65(16):7065-70.
[79]Si ML, Zhu S, Wu H, et al. miR-21-mediated tumor growth. Oncogene,2007, 26(19):2799-803.
[80]Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res,2005,65(14):6029-33.
[81]Lee EJ, Gusev Y, Jiang J, et al. Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer,2007,120(5):1046-54.
[82]Roldo C, Missiaglia E, Hagan JP, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors areassociated with distinctive pathologic features and clinical behavior. J Clin Oncol,2006,24(29):4677-84.
[83]Meng F, Henson R, Lang M, et al. Involvement of human micro-RNA in growth and response to chemotherapy in humancholangiocarcinoma cell lines. Gastroenterology,2006,130(7):2113-29.
[84]Eis PS, Tam W, Sun L, et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A,2005, 102(10):3627-32.
[85]Kluiver J, Poppema S, de Jong D, et al. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J Pathol,2005, 207(2):243-9.
[86]Metzler M, Wilda M, Busch K, et al. High expression of precursor microRNA-155/BIC RNA in children with Burkittlymphoma. Genes Chromosomes Cancer,2004,39(2):167-9.
[87]Yanaihara N, Caplen N, Bowman E, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell,2006,9(3):189-98.
[88]Nikiforova MN, Tseng GC, Steward D, et al. MicroRNA expression profiling of thyroid tumors:biological significance anddiagnostic utility. J Clin Endocrinol Metab,2008,93(5):1600-8.
[89]Habbe N, Koorstra JB, Mendell JT, et al. MicroRNA miR-155 is a biomarker of early pancreatic neoplasia. Cancer Biol Ther,2009,8(4):340-6.
[90]Ryu JK, Hong SM, Karikari CA, et al. Aberrant MicroRNA-155 expression is an early event in the multistep progressionof pancreatic adenocarcinoma. Pancreatology,2010,10(1):66-73.
[91]Gronberg H, Damber L, Damber JE. Familial prostate cancer in Sweden.A nationwide register cohort study. Cancer,1996,77(1):138-43.
[92]Denis L, Morton MS, Griffiths K. Diet and its preventive role in prostatic disease. Eur Urol,1999,35(5-6):377-87.
[93]Fradet Y, Meyer F, Bairati I, et al. Dietary fat and prostate cancer progression and survival. Eur Urol,1999,35(5-6):388-91.
[94]Meyer F, Bairati I, Shadmani R, et al. Dietary fat and prostate cancer survival. Cancer Causes Control,1999,10(4):245-51.
[95]Bott SR. Management of recurrent disease after radical prostatectomy. Prostate Cancer Prostatic Dis,2004,7(3):211-6.
[96]Kindrick AV, Grossfeld GD, Stier DM, et al. Use of imaging tests for staging newly diagnosed prostate cancer:trends from theCaPSURE database. J Urol,1998, 160(6 Pt1):2102-6.
[97]Santos AF, Huang H, Tindall DJ. The androgen receptor:a potential target for therapy of prostate cancer. Steroids,2004,69(2):79-85.
[98]Porkka KP, Pfeiffer MJ, Waltering KK, et al. MicroRNA expression profiling in prostate cancer. Cancer Res,2007,67(13):6130-5.
[99]Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A,2006, 103(7):2257-61.
[100]Ozen M, Creighton CJ, Ozdemir M, et al. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene,2008, 27(12):1788-93.
[101]Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A,2008, 105(30):10513-8.
[102]Lodes MJ, Caraballo M, Suciu D, et al. Detection of cancer with serum miRNAs on an oligonucleotide microarray. PLoS One,2009,4(7):e6229.
[103]Lin SL, Chiang A, Chang D, et al. Loss of mir-146a function in hormone-refractory prostate cancer. RNA,2008,14(3):417-24.
[104]Musiyenko A, Bitko V, Barik S. Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells. J Mol Med (Berl),2008, 86(3):313-22.
[105]Gandellini P, Folini M, Longoni N, et al. miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res,2009,69(6):2287-95.
[106]Varambally S, Cao Q, Mani RS, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science,2008, 322(5908):1695-9.
[107]Raveche ES, Salerno E, Scaglione BJ, et al. Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood,2007, 109(12):5079-86.
[108]Linsley PS, Schelter J, Burchard J, et al. Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol Cell Biol, 2007,27(6):2240-52.
[109]Kong D, Li Y, Wang Z, et al. miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem Cells,2009,27(8):1712-21.
[110]Spahn M, Kneitz S, Scholz CJ, et al. Expression of microRNA-221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence. Int J Cancer,2010,127(2):394-403.
[111]Takeshita F, Patrawala L, Osaki M, et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther,2010,18(l):181-7.
[112]Sylvestre Y, De Guire V, Querido E, et al. An E2F/miR-20a autoregulatory feedback loop. J Biol Chem,2007,282(4):2135-43.
[113]Ambs S, Prueitt RL, Yi M, et al. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res, 2008,68(15):6162-70.
[114]Papagiannakopoulos T, Shapiro A, Kosik KS. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res,2008, 68(19):8164-72.
[115]Lu Z, Liu M, Stribinskis V, et al. MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene,2008,27(31):4373-9.
[116]Yang CH, Yue J, Fan M, et al. IFN induces miR-21 through a signal transducer and activator of transcription 3-dependent pathway as a suppressive negative feedback on IFN-induced apoptosis. Cancer Res,2010,70(20):8108-16.
[117]Parkin DM, Bray F, Ferlay J. Pisani P. Global cancer statistics,2002. CA Cancer J Clin,2005,55(2):74-108. [118]Siegel R, Ward E, Brawley O, et al. Cancer statistics,2011:the impact of eliminating socioeconomic and racialdisparities on premature cancer deaths. CA Cancer J Clin,2011,61(4):212-36.
[119]Stein JP, Quek ML, Skinner DG. Lymphadenectomy for invasive bladder cancer: Ⅰ. historical perspective andcontemporary rationale. BJU Int,2006,97(2):227-31.
[120]Liedberg F, Chebil G, Davidsson T, et al. Intraoperative sentinel node detection improves nodal staging in invasive bladdercancer. J Urol,2006,175(1):84-8; discussion 88-9.
[121]Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term resultsin 1,054 patients. J Clin Oncol,2001, 19(3):666-75.
[122]Shipley WU, Kaufman DS, Zehr E, et al. Selective bladder preservation by combined modality protocol treatment:long-termoutcomes of 190 patients with invasive bladder cancer. Urology,2002,60(1):62-7; discussion 67-8.
[123]Gottardo F, Liu CG, Ferracin M, et al. Micro-RNA profiling in kidney and bladder cancers. Urol Oncol,2007,25(5):387-92.
[124]Dyrskjot L, Ostenfeld MS, Bramsen JB, et al. Genomic profiling of microRNAs in bladder cancer:miR-129 is associated with poor outcome and promotes cell death in vitro. Cancer Res,2009,69(11):4851-60.
[125]Wang G, Chan ES, Kwan BC, et al. Expression of microRNAs in the Urine of Patients With Bladder Cancer. Clin Genitourin Cancer,2012.
[126]Han Y, Chen J, Zhao X, et al. MicroRNA expression signatures of bladder cancer revealed by deep sequencing. PLoS One,2011,6(3):e18286.
[127]夏伟,宋涛,李洁,等.临床膀肮癌组织中miRNA的差异表达研究.军事医学科学院院刊,2010,(06)：540-542.
[128]Yates DR, Rehman I, Abbod MF, et al. Promoter hypermethylation identifies progression risk in bladder cancer. Clin Cancer Res,2007,13(7):2046-53.
[129]Catto JW, Abbod MF, Wild PJ, et al. The application of artificial intelligence to microarray data:identification of a novel gene signature to identify bladder cancer progression. Eur Urol,2010,57(3):398-406.
[130]Veerla S, Lindgren D, Kvist A, et al. MiRNA expression in urothelial carcinomas: important roles of miR-10a, miR-222, miR-125b, miR-7 and miR-452 for tumor stage and metastasis, and frequent homozygous losses of miR-31. Int J Cancer, 2009,124(9):2236-42.
[131]Wiklund ED, Bramsen JB, Hulf T, et al. Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int J Cancer,2011, 128(6):1327-34.
[132]Neely LA, Rieger-Christ KM, Neto BS, et al.A microRNA expression ratio defining the invasive phenotype in bladder tumors. Urol Oncol,2010, 28(1):39-48.
[133]Catto JW, Miah S, Owen HC, et al. Distinct microRNA alterations characterize high- and low-grade bladder cancer. Cancer Res,2009,69(21):8472-81.
[134]Chiyomaru T, Enokida H, Tatarano S, et al. miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer. Br J Cancer,2010,102(5):883-91.
[135]Ichimi T, Enokida H, Okuno Y, et al. Identification of novel microRNA targets based on microRNA signatures in bladder cancer. Int J Cancer,2009, 125(2):345-52.
[136]Huang L, Luo J, Cai Q, et al. MicroRNA-125b suppresses the development of bladder cancer by targeting E2F3. Int J Cancer,2011,128(8):1758-69.
[137]夏伟,宋涛,李洁,等.Mir-200b抑制膀胱癌细胞T24的迁移.军事医学科学院院刊,2010,(05)：433-435.
[138]Lu Q, Lu C, Zhou GP, et al. MicroRNA-221 silencing predisposed human bladder cancer cells to undergo apoptosis induced by TRAIL. Urol Oncol,2010, 28(6):635-41.
[139]Dyrskjot L, Ostenfeld MS, Bramsen JB, et al. Genomic profiling of microRNAs in bladder cancer:miR-129 is associated with poor outcome and promotes cell death in vitro. Cancer Res,2009,69(11):4851-60.
[140]Villadsen SB, Bramsen JB, Ostenfeld MS, et al. The miR-143/-145 cluster regulates plasminogen activator inhibitor-1 in bladdercancer. Br J Cancer,2012, 106(2):366-74.
[141]Jemal A, Siegel R, Xu J, et al. Cancer statistics,2010. CA Cancer J Clin,2010, 60(5):277-300.
[142]Delahunt B, Eble JN, McCredie MR, et al. Morphologic typing of papillary renal cell carcinoma:comparison of growthkinetics and patient survival in 66 cases. Hum Pathol,2001,32(6):590-5.
[143]Redova M, Svoboda M, Slaby O. MicroRNAs and their target gene networks in renal cell carcinoma. Biochem Biophys Res Commun,2011,405(2):153-6.
[144]Dutta KK, Zhong Y, Liu YT, et al. Association of microRNA-34a overexpression with proliferation is cell type-dependent. Cancer Sci,2007,98(12):1845-52.
[145]Juan D, Alexe G, Antes T, et al. Identification of a microRNA panel for clear-cell kidney cancer. Urology,2010,75(4):835-41.
[146]Huang Y, Dai Y, Yang J, et al. Microarray analysis of microRNA expression in renal clear cell carcinoma. Eur J Surg Oncol,2009,35(10):1119-23.
[147]翟庆娜,周亮,余振东,等.大规模平行测序技术筛选人肾细胞癌组织中差异表达microRNAs及其验证.中国肿瘤生物治疗杂志,2011,(03)：306-310.
[148]White NM, Khella HW, Grigull J, et al. miRNA profiling in metastatic renal cell carcinoma reveals a tumour-suppressoreffect for miR-215. Br J Cancer,2011, 105(11):1741-9.
[149]冷慧敏,钱卫平,周亮,等.肾癌中MIR-184的异常表达及意义.北京大学学报(医学版),2011,(04)：509-513.
[150]Chow TF, Mankaruos M, Scorilas A, et al. The miR-17-92 cluster is over expressed in and has an oncogenic effect on renal cell carcinoma. J Urol,2010, 183(2):743-51.
[151]廖凯,洪艳,尹冰德,等.mir-27a、mir-200c及mir-145对肾癌细胞侵袭能力的影响.现代肿瘤医学,2011,(10)：1925-1929.
[152]Saini S, Yamamura S, Majid S, et al. MicroRNA-708 induces apoptosis and suppresses tumorigenicity in renal cancer cells. Cancer Res,2011, 71(19):6208-19.
[153]Zhang A, Liu Y, Shen Y, et al. miR-21 modulates cell apoptosis by targeting multiple genes in renal cell carcinoma. Urology,2011,78(2):474.e13-9.
[154]Li S, Chen T, Zhong Z, et al. microRNA-155 silencing inhibits proliferation and migration and induces apoptosisby upregulating BACH1 in renal cancer cells. Mol Med Report,2012,5(4):949-54.
[155]Nakada C, Matsuura K, Tsukamoto Y, et al. Genome-wide microRNA expression profiling in renal cell carcinoma:significant down-regulation of miR-141 and miR-200c. J Pathol,2008,216(4):418-27.
[156]Petillo D, Kort EJ, Anema J, et al. MicroRNA profiling of human kidney cancer subtypes. Int J Oncol,2009,35(1):109-14.
[157]Youssef YM, White NM, Grigull J, et al. Accurate molecular classification of kidney cancer subtypes using microRNAsignature. Eur Urol,2011,59(5):721-30.
[158]Gillis AJ, Stoop HJ, Hersmus R, et al. High-throughput microRNAome analysis in human germ cell tumours. J Pathol,2007,213(3):319-28.
[159]Looijenga LH, Gillis AJ, Stoop H, et al. Relevance of microRNAs in normal and malignant development, including human testicular germ cell tumours. Int J Androl,2007,30(4):304-14; discussion 314-5.
[160]Cheung HH, Davis AJ, Lee TL, et al. Methylation of an intronic region regulates miR-199a in testicular tumormalignancy. Oncogene,2011,30(31):3404-15.
[161]Lian J, Tian H, Liu L, et al. Downregulation of microRNA-383 is associated with male infertility and promotestesticular embryonal carcinoma cell proliferation by targeting IRF1. Cell Death Dis,2010,1:e94.
[162]Voorhoeve PM, le SC, Schrier M, et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testiculargerm cell tumors. Cell,2006, 124(6):1169-81.
[163]Chen ZH, Zhang GL, Li HR, et al. A panel of five circulating microRNAs as potential biomarkers for prostate cancer. LID-10.1002/pros.22495 [doi]. Prostate, 2012.
[164]Prueitt RL, Yi M, Hudson RS, et al. Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer. Prostate,2008,68(11):1152-64
[165]Takeshita F, Patrawala L, Osaki M, et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther,2010,18(1):181-7.
[166]Hanke M, Hoefig K, Merz H, et al. A robust methodology to study urine microRNA as tumor marker:microRNA-126 and microRNA-182 are related to urinary bladder cancer. Urol Oncol,2010,28(6):655-61.
[167]Yamada Y, Enokida H, Kojima S, et al. MiR-96 and miR-183 detection in urine serve as potential tumor markers of urothelial carcinoma:correlation with stage and grade, and comparison with urinary cytology. Cancer Sci,2011,102(3):522-9.
[168]Wszolek MF, Rieger-Christ KM, Kenney PA, et al.A MicroRNA expression profile defining the invasive bladder tumor phenotype. Urol Oncol, 2011,29(6):794-801.e1.
[169]Wulfken LM, Moritz R, Ohlmann C, et al. MicroRNAs in renal cell carcinoma: diagnostic implications of serum miR-1233 levels. PLoS One,2011,6(9):e25787.
[170]Powers MP, Alvarez K, Kim HJ, et al. Molecular classification of adult renal epithelial neoplasms using microRNA expression and virtual karyotyping. Diagn Mol Pathol,2011,20(2):63-70.
[171]Youssef YM, White NM, Grigull J, et al. Accurate molecular classification of kidney cancer subtypes using microRNA signature. Eur Urol,2011,59(5):721-30.