MiR-200c抑制肾癌细胞增殖和侵袭转移的机制研究
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摘要
第一部分肾透明细胞癌miRNA表达谱的检测及miR-200c与肾癌临床病理参数之间的相关性分析
目的：研究肾透明细胞癌与癌旁正常组织miRNA表达谱的差异,分析(?)miR-200c与肾透明细胞癌临床病理参数的相关性,为肾透明细胞癌的诊断和鉴定诊断提供有用的参考指标,为治疗效果评估和预后预测提供依据。
方法：我们利用包含了851个人类成熟(?)niRNAs探针的生物芯片来检测5对肾透明细胞癌组织与癌旁正常组织中miRNAs的表达,并利用统计学分析方法分析癌组织与癌旁组织miRNAs的表达差异,按筛选条件fold change>2, P<0.05列为表达差异显著。然后利用实时定量PCR法进一步验证25对肾透明细胞癌组织与癌旁正常组织中miR-200c的表达变化,并利用统计学分析方法分析其与病理参数之间的关系。
结果：microarray芯片共发现118个miRNAs在肾透明细胞癌与癌旁正常组织中存在表达差异,其中74个miRNAs表达具有显著差异。74个miRNAs中有30个miRNAs在肾透明细胞癌组织中表达明显上调,另外44个miRNAs表达明显下调。在另外的25对组织中,实时定量PCR显示相对于癌旁正常组织,miR-200c在肾透明细胞癌组织中的表达下降明显,符合(?)nicroarray芯片的结果,但miR-200c的表达变化与肾透明细胞癌病理参数间未见明显相关性。
结论：肾透明细胞癌与癌旁正常组织的miRNAs表达谱具有明显差异,可以为肾透明细胞癌的诊断和与其他肿瘤的鉴别诊断提供有用的参考指标。miR-200c在癌组织中表达明显下调,有可能扮演抑癌基因的角色。
第二部分miR-200c抑制肾癌细胞增殖的机制研究
目的：我们的microarray芯片结果显示肾透明细胞癌组织中(?)miR-200c的表达量明显低于癌旁正常组织,有作为抑癌基因的潜能。深入研究miR-200c在肾癌细胞增殖中的作用及相关机制探讨,为未来肾癌靶向治疗的开发提供理论基础。方法：首先利用实时定量PCR检测三株肾癌细胞中miR-200c的表达量,筛选合适的细胞株,利用包装了hsa-miR-200c的慢病毒感染细胞建立稳定过表达miR-200c的肾癌细胞株模型；然后利用这个细胞模型探索miR-200c对肾癌细胞增殖的影响,MTT法测定细胞增殖曲线,PI染色和流式细胞仪分析细胞周期；再通过生物信息学方法预测与细胞增殖相关的目标靶基因,利用实时定量PCR、Westernblot和荧光素酶报告基因法进行靶基因的验证；最后动物体内实验进一步证实(?)miR-200c对肾癌细胞增殖的影响。
结果：在SN12-PM6、786-0和A-498细胞中,miR-200c的表达量明显低于25个癌旁正常组织的平均表达量。我们利用慢病毒感染SN12-PM6和786-0建立的肾癌细胞模型是成功的,绿色荧光达90%以上,能稳定过表达miR-200c。MTT法测定细胞增殖曲线发现(?)miR-200c可以抑制肾癌细胞的生长,以72小时最明显。PI法染色后流式细胞仪检测发现miR-200c可以使肾癌细胞停滞在G0/G1期,而拮抗miR-200c的表达后,细胞增殖抑制作用能被逆转。Westernblot法证明(?)miR-200c组CDK2的表达量明显低于miR-Ctr组,荧光素酶报告基因法证明CDK23'UTR区存在(?)miR-200c的结合位点。最后动物实验证明miR-200c组肾癌原位移植瘤的肿瘤重量要明显小于miR-Ctr组。
结论：miR-200c能在转录后水平调控CDK2的表达,使肾癌细胞停滞在G0/G1期,从而抑制肾癌细胞的增殖。这为未来肾透明细胞癌靶向治疗的开发研究提供理论基础
第三部分miR-200c调节上皮间质转化参与肾癌细胞侵袭迁移的初步研究
目的：本部分拟研究miR-200c能否调节上皮间质转化过程,起到抑制肾癌细胞侵袭转移的作用,这将有助于深入了解肾癌的转移过程,并可以鉴定到有意义的治疗靶标。
方法：利用第二部分中建立的稳定过表达miR-200c的肾癌细胞株模型,应用(?)answell法检测过表达miR-200c的肾癌细胞侵袭转移能力的改变。实时定量PCR法检测SN12-PM6、786-0细胞和25对肾透明细胞癌组织与癌旁正常组织样本中ZEB1和E-cadherin的表达,分析肾癌细胞和肾癌组织中miR-200c、ZEB1和E-cadherin三者的关系。最后运用实时定量PCR和Westernblot法检测过表达miR-200c后肾癌细胞ZEB1、E-cadherin在mRNA和蛋白水平上表达的变化。
结果：过表达miR-200c后,相比miR-Ctr组,miR-200c组肾癌细胞的侵袭和迁移能力明显下降。在肾癌细胞和肾癌组织中,miR-200c的表达量与ZEB1成负相关,与E-cadherin成正相关。实时定量PCR法结果显示miR-200c组ZEB1mRNA的表达量要明显低于miR-Ctr组,E-cadherin mRNA的表达量则明显上升。在蛋白水平上,westernblot结果显示miR-200c组ZEB1的表达明显下降,E-cadherin的表达则明显上升。
结论：miR-200c可直接靶向作用于ZEB1,降低ZEB1的表达间接使E-cadherin的表达升高,调节上皮间质转化从而抑制肾癌细胞的侵袭和转移。
Part one:Analysis of the miRNAs expression profiles between renal cell carcinoma and adjacent normal tissue
Objective:To investigate different expression profiles of miRNA between clear cell renal cell carcinoma (ccRCC) and adjacent normal renal tissue. Aim to provide a useful reference for the diagnosis and identification indicators for assessing treatment effect of renal cell carcinoma.
Methods:By using a miRNA microarray platform which covers a total of851human miRNAs, the expression profiles of miRNA in five coupled ccRCCs and normal renal tissues were screened. Then miR-200c with significant downregulation was confirmed by quantitative RT-PCR in twenty pairs of ccRCC and matched normal renal tissue, and we analysised the correlation between miR-200c and renal cancer clinicopathological parameters by t-test.
Results:We found that118miRNAs were differentially expressed between five coupled ccRCCs and normal renal tissues, of which74miRNAs were significant difference (fold change>2, P<0.05).30miRNAs were significantly up-regulated in ccRCCs and the other44were down-regulated, In twenty pairs of ccRCC and its matched normal renal tissue, miR-200c was significantly down-regulated in ccRCC, but no correlation with renal cancer clinicopathological parameters.
Conclusion:Our results demonstrated that the different miRNA expression profiles could be a potential reference for the diagnosis and differential diagnosis of renal cell carcinoma. MiR-200c which is commonly down-regulated in ccRCC specimens may affect the development of renal cell carcinama as a potential tumor suppressor gene.
Part two:The mechanism investigation of miR-200c on involving in cell proliferation of renal cancer cells
Abjective:In part one, we observed the expression of miR-200c in renal clear cell carcinoma was significantly lower than the adjacent normal tissue. Here, we continue to study the role of miR-200c in renal cell carcinoma proliferation.
Methods:First, the miR-200c expression of three renal cancer cell lines was detected by qRT-PCR. To investigate the effect of miR-200c in tumor cells, SN12-PM6and786-0cells were transduced with pGCSIL-GFP-hsa-miR-200c to establish cell lines model stably expressing miR-200c. The transduction efficiency was determined by counting fluorescent cells and total cells from6random fields for each condition. Growth Curves and FACS Assays were used to study the role of miR-200c in cell proliferation in this model. Then we used bioinformatic predictions to determine possible targets of miR-200c and confirmed this prediction using qRT-PCR, westerblot, fluorescent reporter assay.
Results:We found that miR-200c was significantly down-regulated in SN12-PM6,786-0and A498cell lines compared with normal tissues. The transduction efficiency was over90%in SN12-PM6cells and786-0cells. qRT-PCR indicated that compared to the control, SN12-PM6miR-200c cells and786-0miR-200c cells had26.4-fold and18.1-fold higher miR-200c expression, respectively. Growth curves and FACS assays indicated that ectopic expression of miR-200c suppressed cell growth and induced arrest in the G0/G1phases of cell cycle in renal cancer cells. When miR-200c was overexpressed, protein level of CDK2was markedly reduced. Conversely, inhibiting miR-200c expression resulted in up-regulation of CDK2protein level. We then confirmed that CDK2, whose3'UTR contained the potential binding site of miR-200c, was the candidate target gene using a fluorescent reporter assay. Furthermore, miR-200c suppressed tumor growth of SN12-PM6cells in nude mice.
Conclusion:Our results showed that miR-200c could induce renal cancer cell arrest in G0/G1phases and inhibited cell proliferation through directly regulating the expression of CDK2at the post-transcriptional level.
Part three:MiR-200c modulates the epithelial-to-mesenchymal transition in human renal cell carcinoma metastasis
Objective:The aim of the present study was to investigate the possible roles of miR-200c in regulating metastasis and to identify its target genes in the renal carcinoma cells.
Methods:To validate the involvement of miR-200c dysregulation in migration and invasion, migration test and invasion test were performed to test the effects of miR-200c. Then we measured the expression of miR-200c, ZEBl, and E-cadherin in SN12-PM6cells,786-0cells, and20pairs of human RCC tissues by qRT-PCR. We used bioinformatic predictions to determine possible targets of miR-200c and confirmed this prediction using qRT-PCR, westerblot.
Results:Functional assays demonstrated that restoration of miR-200c significantly inhibited migration and invasion of SN12-PM6and786-0cells in vitro. Genome-wide gene expression analysis and TargetScan database studies showed that ZEB1which has been shown to promote tumor invasion and migration through E-cadherin gene silencing, is a promising candidate target gene of miRD200c. Overexpression of miR-200c in SN12-PM6and786-0cells was concurrent with downregulation of ZEB1and upregulation of E-cadherin mRNA and protein. The expression of miR-200c was inversely correlated with that of ZEB1but positively correlated with that of E-cadherin in SN12-PM6cells,786-0 cells, and20pairs of human RCC tissues.
Conclution:These observations indicate that miR-200c could regulate ZEB1at the post-transcriptional level to modulate the EMT, inhibiting migration and invasion in SN12-PM6and786-0cancer cells.
目的：研究肾透明细胞癌与癌旁正常组织miRNA表达谱的差异,分析(?)miR-200c与肾透明细胞癌临床病理参数的相关性,为肾透明细胞癌的诊断和鉴定诊断提供有用的参考指标,为治疗效果评估和预后预测提供依据。
方法：我们利用包含了851个人类成熟(?)niRNAs探针的生物芯片来检测5对肾透明细胞癌组织与癌旁正常组织中miRNAs的表达,并利用统计学分析方法分析癌组织与癌旁组织miRNAs的表达差异,按筛选条件fold change>2, P<0.05列为表达差异显著。然后利用实时定量PCR法进一步验证25对肾透明细胞癌组织与癌旁正常组织中miR-200c的表达变化,并利用统计学分析方法分析其与病理参数之间的关系。
结果：microarray芯片共发现118个miRNAs在肾透明细胞癌与癌旁正常组织中存在表达差异,其中74个miRNAs表达具有显著差异。74个miRNAs中有30个miRNAs在肾透明细胞癌组织中表达明显上调,另外44个miRNAs表达明显下调。在另外的25对组织中,实时定量PCR显示相对于癌旁正常组织,miR-200c在肾透明细胞癌组织中的表达下降明显,符合(?)nicroarray芯片的结果,但miR-200c的表达变化与肾透明细胞癌病理参数间未见明显相关性。
结论：肾透明细胞癌与癌旁正常组织的miRNAs表达谱具有明显差异,可以为肾透明细胞癌的诊断和与其他肿瘤的鉴别诊断提供有用的参考指标。miR-200c在癌组织中表达明显下调,有可能扮演抑癌基因的角色。
第二部分miR-200c抑制肾癌细胞增殖的机制研究
目的：我们的microarray芯片结果显示肾透明细胞癌组织中(?)miR-200c的表达量明显低于癌旁正常组织,有作为抑癌基因的潜能。深入研究miR-200c在肾癌细胞增殖中的作用及相关机制探讨,为未来肾癌靶向治疗的开发提供理论基础。方法：首先利用实时定量PCR检测三株肾癌细胞中miR-200c的表达量,筛选合适的细胞株,利用包装了hsa-miR-200c的慢病毒感染细胞建立稳定过表达miR-200c的肾癌细胞株模型；然后利用这个细胞模型探索miR-200c对肾癌细胞增殖的影响,MTT法测定细胞增殖曲线,PI染色和流式细胞仪分析细胞周期；再通过生物信息学方法预测与细胞增殖相关的目标靶基因,利用实时定量PCR、Westernblot和荧光素酶报告基因法进行靶基因的验证；最后动物体内实验进一步证实(?)miR-200c对肾癌细胞增殖的影响。
结果：在SN12-PM6、786-0和A-498细胞中,miR-200c的表达量明显低于25个癌旁正常组织的平均表达量。我们利用慢病毒感染SN12-PM6和786-0建立的肾癌细胞模型是成功的,绿色荧光达90%以上,能稳定过表达miR-200c。MTT法测定细胞增殖曲线发现(?)miR-200c可以抑制肾癌细胞的生长,以72小时最明显。PI法染色后流式细胞仪检测发现miR-200c可以使肾癌细胞停滞在G0/G1期,而拮抗miR-200c的表达后,细胞增殖抑制作用能被逆转。Westernblot法证明(?)miR-200c组CDK2的表达量明显低于miR-Ctr组,荧光素酶报告基因法证明CDK23'UTR区存在(?)miR-200c的结合位点。最后动物实验证明miR-200c组肾癌原位移植瘤的肿瘤重量要明显小于miR-Ctr组。
结论：miR-200c能在转录后水平调控CDK2的表达,使肾癌细胞停滞在G0/G1期,从而抑制肾癌细胞的增殖。这为未来肾透明细胞癌靶向治疗的开发研究提供理论基础
第三部分miR-200c调节上皮间质转化参与肾癌细胞侵袭迁移的初步研究
目的：本部分拟研究miR-200c能否调节上皮间质转化过程,起到抑制肾癌细胞侵袭转移的作用,这将有助于深入了解肾癌的转移过程,并可以鉴定到有意义的治疗靶标。
方法：利用第二部分中建立的稳定过表达miR-200c的肾癌细胞株模型,应用(?)answell法检测过表达miR-200c的肾癌细胞侵袭转移能力的改变。实时定量PCR法检测SN12-PM6、786-0细胞和25对肾透明细胞癌组织与癌旁正常组织样本中ZEB1和E-cadherin的表达,分析肾癌细胞和肾癌组织中miR-200c、ZEB1和E-cadherin三者的关系。最后运用实时定量PCR和Westernblot法检测过表达miR-200c后肾癌细胞ZEB1、E-cadherin在mRNA和蛋白水平上表达的变化。
结果：过表达miR-200c后,相比miR-Ctr组,miR-200c组肾癌细胞的侵袭和迁移能力明显下降。在肾癌细胞和肾癌组织中,miR-200c的表达量与ZEB1成负相关,与E-cadherin成正相关。实时定量PCR法结果显示miR-200c组ZEB1mRNA的表达量要明显低于miR-Ctr组,E-cadherin mRNA的表达量则明显上升。在蛋白水平上,westernblot结果显示miR-200c组ZEB1的表达明显下降,E-cadherin的表达则明显上升。
结论：miR-200c可直接靶向作用于ZEB1,降低ZEB1的表达间接使E-cadherin的表达升高,调节上皮间质转化从而抑制肾癌细胞的侵袭和转移。
Part one:Analysis of the miRNAs expression profiles between renal cell carcinoma and adjacent normal tissue
Objective:To investigate different expression profiles of miRNA between clear cell renal cell carcinoma (ccRCC) and adjacent normal renal tissue. Aim to provide a useful reference for the diagnosis and identification indicators for assessing treatment effect of renal cell carcinoma.
Methods:By using a miRNA microarray platform which covers a total of851human miRNAs, the expression profiles of miRNA in five coupled ccRCCs and normal renal tissues were screened. Then miR-200c with significant downregulation was confirmed by quantitative RT-PCR in twenty pairs of ccRCC and matched normal renal tissue, and we analysised the correlation between miR-200c and renal cancer clinicopathological parameters by t-test.
Results:We found that118miRNAs were differentially expressed between five coupled ccRCCs and normal renal tissues, of which74miRNAs were significant difference (fold change>2, P<0.05).30miRNAs were significantly up-regulated in ccRCCs and the other44were down-regulated, In twenty pairs of ccRCC and its matched normal renal tissue, miR-200c was significantly down-regulated in ccRCC, but no correlation with renal cancer clinicopathological parameters.
Conclusion:Our results demonstrated that the different miRNA expression profiles could be a potential reference for the diagnosis and differential diagnosis of renal cell carcinoma. MiR-200c which is commonly down-regulated in ccRCC specimens may affect the development of renal cell carcinama as a potential tumor suppressor gene.
Part two:The mechanism investigation of miR-200c on involving in cell proliferation of renal cancer cells
Abjective:In part one, we observed the expression of miR-200c in renal clear cell carcinoma was significantly lower than the adjacent normal tissue. Here, we continue to study the role of miR-200c in renal cell carcinoma proliferation.
Methods:First, the miR-200c expression of three renal cancer cell lines was detected by qRT-PCR. To investigate the effect of miR-200c in tumor cells, SN12-PM6and786-0cells were transduced with pGCSIL-GFP-hsa-miR-200c to establish cell lines model stably expressing miR-200c. The transduction efficiency was determined by counting fluorescent cells and total cells from6random fields for each condition. Growth Curves and FACS Assays were used to study the role of miR-200c in cell proliferation in this model. Then we used bioinformatic predictions to determine possible targets of miR-200c and confirmed this prediction using qRT-PCR, westerblot, fluorescent reporter assay.
Results:We found that miR-200c was significantly down-regulated in SN12-PM6,786-0and A498cell lines compared with normal tissues. The transduction efficiency was over90%in SN12-PM6cells and786-0cells. qRT-PCR indicated that compared to the control, SN12-PM6miR-200c cells and786-0miR-200c cells had26.4-fold and18.1-fold higher miR-200c expression, respectively. Growth curves and FACS assays indicated that ectopic expression of miR-200c suppressed cell growth and induced arrest in the G0/G1phases of cell cycle in renal cancer cells. When miR-200c was overexpressed, protein level of CDK2was markedly reduced. Conversely, inhibiting miR-200c expression resulted in up-regulation of CDK2protein level. We then confirmed that CDK2, whose3'UTR contained the potential binding site of miR-200c, was the candidate target gene using a fluorescent reporter assay. Furthermore, miR-200c suppressed tumor growth of SN12-PM6cells in nude mice.
Conclusion:Our results showed that miR-200c could induce renal cancer cell arrest in G0/G1phases and inhibited cell proliferation through directly regulating the expression of CDK2at the post-transcriptional level.
Part three:MiR-200c modulates the epithelial-to-mesenchymal transition in human renal cell carcinoma metastasis
Objective:The aim of the present study was to investigate the possible roles of miR-200c in regulating metastasis and to identify its target genes in the renal carcinoma cells.
Methods:To validate the involvement of miR-200c dysregulation in migration and invasion, migration test and invasion test were performed to test the effects of miR-200c. Then we measured the expression of miR-200c, ZEBl, and E-cadherin in SN12-PM6cells,786-0cells, and20pairs of human RCC tissues by qRT-PCR. We used bioinformatic predictions to determine possible targets of miR-200c and confirmed this prediction using qRT-PCR, westerblot.
Results:Functional assays demonstrated that restoration of miR-200c significantly inhibited migration and invasion of SN12-PM6and786-0cells in vitro. Genome-wide gene expression analysis and TargetScan database studies showed that ZEB1which has been shown to promote tumor invasion and migration through E-cadherin gene silencing, is a promising candidate target gene of miRD200c. Overexpression of miR-200c in SN12-PM6and786-0cells was concurrent with downregulation of ZEB1and upregulation of E-cadherin mRNA and protein. The expression of miR-200c was inversely correlated with that of ZEB1but positively correlated with that of E-cadherin in SN12-PM6cells,786-0 cells, and20pairs of human RCC tissues.
Conclution:These observations indicate that miR-200c could regulate ZEB1at the post-transcriptional level to modulate the EMT, inhibiting migration and invasion in SN12-PM6and786-0cancer cells.
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17. Bandres E, Cubedo E, Agirre X, et al: Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer 5:29,2006.
18. Guo Y, Chen Z, Zhang L, et al: Distinctive microRNA profiles relating to patient survival in esophageal squamous cell carcinoma. Cancer Res 68:26-33,2008.
19. Slaby O, Svoboda M, Fabian P, et al: Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology 72: 397-402,2007.
20. Ladeiro Y, Couchy G, Balabaud C, et al: MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology 47:1955-1963,2008.
21. Hatley ME, Patrick DM, Garcia MR, et al: Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell 18:282-293,
22. Wang XC, Tian LL, Wu HL, et al: Expression of miRNA-130a in nonsmall cell lung cancer. Am J Med Sci 340:385-388,
23. Chen X, Ba Y, Ma L, et al: Characterization of microRNAs in serum:a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18:997-1006,2008.
24. Redova M, Poprach A, Nekvindova J, et al: Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma. J Transl Med 10:55,
25. Zhao A, Li G, Peoc'h M, Genin C and Gigante M:Serum miR-210 as a novel biomarker for molecular diagnosis of clear cell renal cell carcinoma. Exp Mol Pathol 94:115-120,
1. Berezikov E, van Tetering G, Verheul M, et al: Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis. Genome Res 16: 1289-1298,2006.
2. Ambros V:microRNAs:tiny regulators with great potential. Cell 107:823-826,2001.
3. Cairns P:Renal cell carcinoma. Cancer Biomark 9:461-473,
4. Zhang B, Pan X, Cobb GP and Anderson TA:microRNAs as oncogenes and tumor suppressors. Dev Biol 302:1-12,2007.
5. Ma L:Role of miR-10b in breast cancer metastasis. Breast Cancer Res 12:210,
6. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST and Patel T:MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647-658,2007.
7. Vermeulen K, Van Bockstaele DR and Berneman ZN:The cell cycle:a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36:131-149, 2003.
8. Carleton M, Cleary MA and Linsley PS:MicroRNAs and cell cycle regulation. Cell Cycle 6:2127-2132,2007.
9. Li A and Blow JJ:The origin of CDK regulation. Nat Cell Biol 3:E182-184,2001.
10. Santamaria D, Barriere C, Cerqueira A, et al: Cdkl is sufficient to drive the mammalian cell cycle. Nature 448:811-815,2007.
11. Ortega S, Prieto I, Odajima J, et al: Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 35:25-31,2003.
12. Campaner S, Doni M, Hydbring P, et al: Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat Cell Biol 12:54-59; sup pp 51-14,
13. Hydbring P and Larsson LG:Tipping the balance:Cdk2 enables Myc to suppress senescence. Cancer Res 70:6687-6691,
14. Bartel DP:MicroRNAs:target recognition and regulatory functions. Cell 136: 215-233,2009.
15. Zhang X, Zhu W, Zhang J, et al: MicroRNA-650 targets ING4 to promote gastric cancer tumorigenicity. Biochem Biophys Res Commun 395:275-280,
16. Xu T, Zhu Y, Xiong Y, Ge YY, Yun JP and Zhuang SM:MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells. Hepatology 50:113-121,2009.
17. Liu XY:Targeting gene-virotherapy of cancer and its prosperity. Cell Res 16:879-886, 2006.
18. Hutvagner G, Simard MJ, Mello CC and Zamore PD:Sequence-specific inhibition of small RNA function. PLoS Biol 2:E98,2004.
19. Krutzfeldt J, Rajewsky N, Braich R, et al: Silencing of microRNAs in vivo with 'antagomirs'. Nature 438:685-689,2005.
20. Schickel R, Park SM, Murmann AE and Peter ME:miR-200c regulates induction of apoptosis through CD95 by targeting FAP-1. Mol Cell 38:908-915,
21. Hurteau GJ, Carlson JA, Roos E and Brock GJ:Stable expression of miR-200c alone is sufficient to regulate TCF8 (ZEB1) and restore E-cadherin expression. Cell Cycle 8: 2064-2069,2009.
22. Hurteau GJ, Carlson JA, Spivack SD and Brock GJ:Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res 67:7972-7976,2007.
1. Cairns P:Renal cell carcinoma. Cancer Biomark 9:461-473,
2. Thiery JP, Acloque H, Huang RY and Nieto MA:Epithelial-mesenchymal transitions in development and disease. Cell 139:871-890,2009.
3. Kalluri R and Weinberg RA:The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420-1428,2009.
4. Savagner P:The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol 21 Suppl 7:vii89-92,
5. Bonnomet A, Brysse A, Tachsidis A, et al: Epithelial-to-mesenchymal transitions and circulating tumor cells. J Mammary Gland Biol Neoplasia 15:261-273,
6. Micalizzi DS, Farabaugh SM and Ford HL:Epithelial-mesenchymal transition in cancer:parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia 15:117-134,
7. Iwatsuki M, Mimori K, Yokobori T, et al: Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci 101:293-299,
8. Micalizzi DS and Ford HL:Epithelial-mesenchymal transition in development and cancer. Future Oncol 5:1129-1143,2009.
9. Arima Y, Inoue Y, Shibata T, et al: Rb depletion results in deregulation of E-cadherin and induction of cellular phenotypic changes that are characteristic of the epithelial-to-mesenchymal transition. Cancer Res 68:5104-5112,2008.
10. Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S and Nakshatri H: NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells:potential involvement of ZEB-1 and ZEB-2. Oncogene 26:711-724,2007.
11. Hur K, Toiyama Y, Takahashi M, et al: MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis. Gut
12. Yu J, Ohuchida K, Mizumoto K, et al: MicroRNA, hsa-miR-200c, is an independent prognostic factor in pancreatic cancer and its upregulation inhibits pancreatic cancer invasion but increases cell proliferation. Mol Cancer 9:169,
13. 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 216:418-427,2008.
14. Korpal M and Kang Y:The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biol 5:115-119,2008.
15. Mongroo PS and Rustgi AK:The role of the miR-200 family in epithelial-mesenchymal transition. Cancer Biol Ther 10:219-222,
16. Hurteau GJ, Carlson JA, Roos E and Brock GJ:Stable expression of miR-200c alone is sufficient to regulate TCF8 (ZEB1) and restore E-cadherin expression. Cell Cycle 8: 2064-2069,2009.
17. Chen ML, Liang LS and Wang XK:miR-200c inhibits invasion and migration in human colon cancer cells SW480/620 by targeting ZEB1. Clin Exp Metastasis 29: 457-469,
18. Hurteau GJ, Carlson JA, Spivack SD and Brock GJ:Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res 67:7972-7976,2007.
19. Subramanian G, Schwarz RE, Higgins L, et al: Targeting endogenous transforming growth factor beta receptor signaling in SMAD4-deficient human pancreatic carcinoma cells inhibits their invasive phenotypel. Cancer Res 64:5200-5211,2004.
20. Zeisberg M, Hanai J, Sugimoto H, et al: BMP-7 counteracts TGF-betal-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9: 964-968,2003.
1. Gottardo F, Liu CG, Ferracin M, et al: Micro-RNA profiling in kidney and bladder cancers. Urol Oncol 25:387-392,2007.
2. Cairns P:Renal cell carcinoma. Cancer Biomark 9:461-473,
3. Escudier B:Advanced renal cell carcinoma:current and emerging management strategies. Drugs 67:1257-1264,2007.
4. Lee RC, Feinbaum RL and Ambros V:The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843-854, 1993.
5. Ambros V:microRNAs:tiny regulators with great potential. Cell 107:823-826,2001.
6. Ambros V, Bartel B, Bartel DP, et al: A uniform system for microRNA annotation. RNA 9:277-279,2003.
7. Gregory RI and Shiekhattar R:MicroRNA biogenesis and cancer. Cancer Res 65: 3509-3512,2005.
8. Berezikov E, Cuppen E and Plasterk RH:Approaches to microRNA discovery. Nat Genet 38 Suppl:S2-7,2006.
9. Lund E, Guttinger S, Calado A, Dahlberg JE and Kutay U:Nuclear export of microRNA precursors. Science 303:95-98,2004.
10. Neilson JR, Zheng GX, Burge CB and Sharp PA:Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev 21:578-589,2007.
11. Berezikov E, van Tetering G, Verheul M, et al: Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis. Genome Res 16: 1289-1298,2006.
12. Vasudevan S, Tong Y and Steitz JA:Switching from repression to activation: microRNAs can up-regulate translation. Science 318:1931-1934,2007.
13. Nelson KM and Weiss GJ:MicroRNAs and cancer:past, present, and potential future. Mol Cancer Ther 7:3655-3660,2008.
14. Bartel DP:MicroRNAs:target recognition and regulatory functions. Cell 136: 215-233,2009.
15. Datta J, Kutay H, Nasser MW, et al: Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res 68:5049-5058,2008.
16. Deng S, Calin GA, Croce CM, Coukos G and Zhang L:Mechanisms of microRNA deregulation in human cancer. Cell Cycle 7:2643-2646,2008.
17. Esquela-Kerscher A and Slack FJ:Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer 6:259-269,2006.
18. Kloosterman WP and Plasterk RH:The diverse functions of microRNAs in animal development and disease. Dev Cell 11:441-450,2006.
19. 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 103:2257-2261,2006.
20. Zhang B, Pan X, Cobb GP and Anderson TA:microRNAs as oncogenes and tumor suppressors. Dev Biol 302:1-12,2007.
21. Gaur A, Jewell DA, Liang Y, et al: Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res 67:2456-2468, 2007.
22. Han M, Wang Y, Liu M, et al: MiR-21 regulates epithelial-mesenchymal transition phenotype and hypoxia-inducible factor-1 alpha expression in third-sphere forming breast cancer stem cell-like cells. Cancer Sci 103:1058-1064,
23. Schetter AJ, Leung SY, Sohn JJ, et al: MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299:425-436, 2008.
24. Asangani IA, Rasheed SA, Nikolova DA, et al: MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27:2128-2136,2008.
25. Connolly EC, Van Doorslaer K, Rogler LE and Rogler CE:Overexpression of miR-21 promotes an in vitro metastatic phenotype by targeting the tumor suppressor RHOB. Mol Cancer Res 8:691-700,
26. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST and Patel T:MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647-658,2007.
27. Ma L:Role of miR-10b in breast cancer metastasis. Breast Cancer Res 12:210,
28. 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 102:3627-3632,2005.
29. 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 64:3753-3756,2004.
30. Johnson SM, Grosshans H, Shingara J, et al: RAS is regulated by the let-7 microRNA family. Cell 120:635-647,2005.
31. Akao Y, Nakagawa Y and Naoe T:MicroRNA-143 and-145 in colon cancer. DNA Cell Biol 26:311-320,2007.
32. Shi B, Sepp-Lorenzino L, Prisco M, Linsley P, deAngelis T and Baserga R:Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells. J Biol Chem 282:32582-32590,2007.
33. Linsley PS, Schelter J, Burchard J, et al: Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol Cell Biol 27:2240-2252, 2007.
34. 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 216:418-427,2008.
35. Wotschofsky Z, Busch J, Jung M, et al: Diagnostic and prognostic potential of differentially expressed miRNAs between metastatic and non-metastatic renal cell carcinoma at the time of nephrectomy. Clin Chim Acta 416:5-10,
36. Faragalla H, Youssef YM, Scorilas A, et al: The clinical utility of miR-21 as a diagnostic and prognostic marker for renal cell carcinoma. J Mol Diagn 14:385-392,
37. Chen X, Ba Y, Ma L, et al: Characterization of microRNAs in serum:a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18:997-1006,2008.
38. Zhao A, Li G, Peoc'h M, Genin C and Gigante M:Serum miR-210 as a novel biomarker for molecular diagnosis of clear cell renal cell carcinoma. Exp Mol Pathol 94:115-120,
39. He L, Fan C, Gillis A, et al: Co-existence of high levels of the PTEN protein with enhanced Akt activation in renal cell carcinoma. Biochim Biophys Acta 1772: 1134-1142,2007.
40. Hager M, Haufe H, Kemmerling R, et al: Increased activated Akt expression in renal cell carcinomas and prognosis. J Cell Mol Med 13:2181-2188,2009.
41. Cui L, Zhou H, Zhao H, et al: MicroRNA-99a induces G1-phase cell cycle arrest and suppresses tumorigenicity in renal cell carcinoma. BMC Cancer 12:546,
42. Pantuck AJ, Seligson DB, Klatte T, et al: Prognostic relevance of the mTOR pathway in renal cell carcinoma:implications for molecular patient selection for targeted therapy. Cancer 109:2257-2267,2007.
43. Zaman MS, Thamminana S, Shahryari V, et al: Inhibition of PTEN gene expression by oncogenic miR-23b-3p in renal cancer. PLoS One 7:e50203,
44. Wu C, Jin B, Chen L, et al: MiR-30d induces apoptosis and is regulated by the Akt/FOXO pathway in renal cell carcinoma. Cell Signal 25:1212-1221,
45. Yamasaki T, Seki N, Yoshino H, et al: microRNA-218 inhibits cell migration and invasion in renal cell carcinoma through targeting caveolin-2 involved in focal adhesion pathway. J Urol
2. Nelson KM and Weiss GJ:MicroRNAs and cancer:past, present, and potential future. Mol Cancer Ther 7:3655-3660,2008.
3. Schickel R, Boyerinas B, Park SM and Peter ME:MicroRNAs:key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene 27: 5959-5974,2008.
4. Ambros V:microRNAs:tiny regulators with great potential. Cell 107:823-826,2001.
5. Bartel DP:MicroRNAs:target recognition and regulatory functions. Cell 136: 215-233,2009.
6. Calin GA and Croce CM:MicroRNA signatures in human cancers. Nat Rev Cancer 6: 857-866,2006.
7. Zhang B, Pan X, Cobb GP and Anderson TA:microRNAs as oncogenes and tumor suppressors. Dev Biol 302:1-12,2007.
8. Li W and Ruan K:MicroRNA detection by microarray. Anal Bioanal Chem 394: 1117-1124,2009.
9. Gottardo F, Liu CG, Ferracin M, et al. Micro-RNA profiling in kidney and bladder cancers. Urol Oncol 25:387-392,2007.
10. 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 216:418-427,2008.
11. Park SM, Gaur AB, Lengyel E and Peter ME:The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22:894-907,2008.
12. Wu W, Sun M, Zou GM and Chen J:MicroRNA and cancer:Current status and prospective. Int J Cancer 120:953-960,2007.
13. Gramantieri L, Ferracin M, Fornari F, et al: Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res 67:6092-6099,2007.
14. Du Y, Xu Y, Ding L, et al: Down-regulation of miR-141 in gastric cancer and its involvement in cell growth. J Gastroenterol 44:556-561,2009.
15. Iorio MV, Visone R, Di Leva G, et al: MicroRNA signatures in human ovarian cancer. Cancer Res 67:8699-8707,2007.
16. Meng F, Henson R, Lang M, et al: Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 130:2113-2129,2006.
17. Bandres E, Cubedo E, Agirre X, et al: Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer 5:29,2006.
18. Guo Y, Chen Z, Zhang L, et al: Distinctive microRNA profiles relating to patient survival in esophageal squamous cell carcinoma. Cancer Res 68:26-33,2008.
19. Slaby O, Svoboda M, Fabian P, et al: Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology 72: 397-402,2007.
20. Ladeiro Y, Couchy G, Balabaud C, et al: MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology 47:1955-1963,2008.
21. Hatley ME, Patrick DM, Garcia MR, et al: Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell 18:282-293,
22. Wang XC, Tian LL, Wu HL, et al: Expression of miRNA-130a in nonsmall cell lung cancer. Am J Med Sci 340:385-388,
23. Chen X, Ba Y, Ma L, et al: Characterization of microRNAs in serum:a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18:997-1006,2008.
24. Redova M, Poprach A, Nekvindova J, et al: Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma. J Transl Med 10:55,
25. Zhao A, Li G, Peoc'h M, Genin C and Gigante M:Serum miR-210 as a novel biomarker for molecular diagnosis of clear cell renal cell carcinoma. Exp Mol Pathol 94:115-120,
1. Berezikov E, van Tetering G, Verheul M, et al: Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis. Genome Res 16: 1289-1298,2006.
2. Ambros V:microRNAs:tiny regulators with great potential. Cell 107:823-826,2001.
3. Cairns P:Renal cell carcinoma. Cancer Biomark 9:461-473,
4. Zhang B, Pan X, Cobb GP and Anderson TA:microRNAs as oncogenes and tumor suppressors. Dev Biol 302:1-12,2007.
5. Ma L:Role of miR-10b in breast cancer metastasis. Breast Cancer Res 12:210,
6. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST and Patel T:MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647-658,2007.
7. Vermeulen K, Van Bockstaele DR and Berneman ZN:The cell cycle:a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36:131-149, 2003.
8. Carleton M, Cleary MA and Linsley PS:MicroRNAs and cell cycle regulation. Cell Cycle 6:2127-2132,2007.
9. Li A and Blow JJ:The origin of CDK regulation. Nat Cell Biol 3:E182-184,2001.
10. Santamaria D, Barriere C, Cerqueira A, et al: Cdkl is sufficient to drive the mammalian cell cycle. Nature 448:811-815,2007.
11. Ortega S, Prieto I, Odajima J, et al: Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 35:25-31,2003.
12. Campaner S, Doni M, Hydbring P, et al: Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat Cell Biol 12:54-59; sup pp 51-14,
13. Hydbring P and Larsson LG:Tipping the balance:Cdk2 enables Myc to suppress senescence. Cancer Res 70:6687-6691,
14. Bartel DP:MicroRNAs:target recognition and regulatory functions. Cell 136: 215-233,2009.
15. Zhang X, Zhu W, Zhang J, et al: MicroRNA-650 targets ING4 to promote gastric cancer tumorigenicity. Biochem Biophys Res Commun 395:275-280,
16. Xu T, Zhu Y, Xiong Y, Ge YY, Yun JP and Zhuang SM:MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells. Hepatology 50:113-121,2009.
17. Liu XY:Targeting gene-virotherapy of cancer and its prosperity. Cell Res 16:879-886, 2006.
18. Hutvagner G, Simard MJ, Mello CC and Zamore PD:Sequence-specific inhibition of small RNA function. PLoS Biol 2:E98,2004.
19. Krutzfeldt J, Rajewsky N, Braich R, et al: Silencing of microRNAs in vivo with 'antagomirs'. Nature 438:685-689,2005.
20. Schickel R, Park SM, Murmann AE and Peter ME:miR-200c regulates induction of apoptosis through CD95 by targeting FAP-1. Mol Cell 38:908-915,
21. Hurteau GJ, Carlson JA, Roos E and Brock GJ:Stable expression of miR-200c alone is sufficient to regulate TCF8 (ZEB1) and restore E-cadherin expression. Cell Cycle 8: 2064-2069,2009.
22. Hurteau GJ, Carlson JA, Spivack SD and Brock GJ:Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res 67:7972-7976,2007.
1. Cairns P:Renal cell carcinoma. Cancer Biomark 9:461-473,
2. Thiery JP, Acloque H, Huang RY and Nieto MA:Epithelial-mesenchymal transitions in development and disease. Cell 139:871-890,2009.
3. Kalluri R and Weinberg RA:The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420-1428,2009.
4. Savagner P:The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol 21 Suppl 7:vii89-92,
5. Bonnomet A, Brysse A, Tachsidis A, et al: Epithelial-to-mesenchymal transitions and circulating tumor cells. J Mammary Gland Biol Neoplasia 15:261-273,
6. Micalizzi DS, Farabaugh SM and Ford HL:Epithelial-mesenchymal transition in cancer:parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia 15:117-134,
7. Iwatsuki M, Mimori K, Yokobori T, et al: Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci 101:293-299,
8. Micalizzi DS and Ford HL:Epithelial-mesenchymal transition in development and cancer. Future Oncol 5:1129-1143,2009.
9. Arima Y, Inoue Y, Shibata T, et al: Rb depletion results in deregulation of E-cadherin and induction of cellular phenotypic changes that are characteristic of the epithelial-to-mesenchymal transition. Cancer Res 68:5104-5112,2008.
10. Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S and Nakshatri H: NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells:potential involvement of ZEB-1 and ZEB-2. Oncogene 26:711-724,2007.
11. Hur K, Toiyama Y, Takahashi M, et al: MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis. Gut
12. Yu J, Ohuchida K, Mizumoto K, et al: MicroRNA, hsa-miR-200c, is an independent prognostic factor in pancreatic cancer and its upregulation inhibits pancreatic cancer invasion but increases cell proliferation. Mol Cancer 9:169,
13. 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 216:418-427,2008.
14. Korpal M and Kang Y:The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biol 5:115-119,2008.
15. Mongroo PS and Rustgi AK:The role of the miR-200 family in epithelial-mesenchymal transition. Cancer Biol Ther 10:219-222,
16. Hurteau GJ, Carlson JA, Roos E and Brock GJ:Stable expression of miR-200c alone is sufficient to regulate TCF8 (ZEB1) and restore E-cadherin expression. Cell Cycle 8: 2064-2069,2009.
17. Chen ML, Liang LS and Wang XK:miR-200c inhibits invasion and migration in human colon cancer cells SW480/620 by targeting ZEB1. Clin Exp Metastasis 29: 457-469,
18. Hurteau GJ, Carlson JA, Spivack SD and Brock GJ:Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res 67:7972-7976,2007.
19. Subramanian G, Schwarz RE, Higgins L, et al: Targeting endogenous transforming growth factor beta receptor signaling in SMAD4-deficient human pancreatic carcinoma cells inhibits their invasive phenotypel. Cancer Res 64:5200-5211,2004.
20. Zeisberg M, Hanai J, Sugimoto H, et al: BMP-7 counteracts TGF-betal-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9: 964-968,2003.
1. Gottardo F, Liu CG, Ferracin M, et al: Micro-RNA profiling in kidney and bladder cancers. Urol Oncol 25:387-392,2007.
2. Cairns P:Renal cell carcinoma. Cancer Biomark 9:461-473,
3. Escudier B:Advanced renal cell carcinoma:current and emerging management strategies. Drugs 67:1257-1264,2007.
4. Lee RC, Feinbaum RL and Ambros V:The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843-854, 1993.
5. Ambros V:microRNAs:tiny regulators with great potential. Cell 107:823-826,2001.
6. Ambros V, Bartel B, Bartel DP, et al: A uniform system for microRNA annotation. RNA 9:277-279,2003.
7. Gregory RI and Shiekhattar R:MicroRNA biogenesis and cancer. Cancer Res 65: 3509-3512,2005.
8. Berezikov E, Cuppen E and Plasterk RH:Approaches to microRNA discovery. Nat Genet 38 Suppl:S2-7,2006.
9. Lund E, Guttinger S, Calado A, Dahlberg JE and Kutay U:Nuclear export of microRNA precursors. Science 303:95-98,2004.
10. Neilson JR, Zheng GX, Burge CB and Sharp PA:Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev 21:578-589,2007.
11. Berezikov E, van Tetering G, Verheul M, et al: Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis. Genome Res 16: 1289-1298,2006.
12. Vasudevan S, Tong Y and Steitz JA:Switching from repression to activation: microRNAs can up-regulate translation. Science 318:1931-1934,2007.
13. Nelson KM and Weiss GJ:MicroRNAs and cancer:past, present, and potential future. Mol Cancer Ther 7:3655-3660,2008.
14. Bartel DP:MicroRNAs:target recognition and regulatory functions. Cell 136: 215-233,2009.
15. Datta J, Kutay H, Nasser MW, et al: Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res 68:5049-5058,2008.
16. Deng S, Calin GA, Croce CM, Coukos G and Zhang L:Mechanisms of microRNA deregulation in human cancer. Cell Cycle 7:2643-2646,2008.
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