miRNA-mRNA差异表达与卵巢癌多药耐药关系的研究
|
摘要
卵巢癌在女性生殖道恶性肿瘤发病率中占第三位，但是死亡率高居第一。化疗是治疗卵巢上皮癌重要手段之一，但多药耐药的产生又是导致化疗失败的中心环节。卵巢上皮癌多药耐药机制十分复杂，目前研究认为可能涉及肿瘤细胞内化疗药物的外排、DNA损伤与修复、细胞凋亡异常和信号传导通路障碍等分子机制，但是至今仍未找到安全有效的逆转耐药靶点。本研究拟通过运用miRNA芯片技术和基因芯片技术，以及生物信息学等多样化研究手段，从临床到基础研究，然后回归临床的研究桥梁，阐述卵巢上皮癌多药耐药分子机制，为寻找安全有效的逆转卵巢上皮癌多药耐药治疗靶点提供理论基础。
研究目的：筛选卵巢上皮癌多药耐药相关miRNA表达谱。
材料和方法：采用Agilent miRNA芯片，检测5例卵巢上皮癌耐药组织、5例敏感组织、5例卵巢良性肿瘤和5例正常卵巢组织的miRNA表达情况，运用Fc差异倍数，获得了卵巢上皮癌耐药组和敏感组差异大于2倍的上调或下调miRNA。用多个在线软件分别预测上调和下调差异miRNA对应的靶基因，并运用GO分析和Pathway通路富集等生物信息学方法分析预测到的靶基因潜在的生物学功能和参与的信号通路。用QRT-PCR验证芯片结果，并扩大样本量检测目的miRNA的表达情况，并分析miRNA表达水平与临床病理因素关系。
结果：miRNA芯片筛选出与卵巢上皮癌多药耐药相关的差异表达miRNA共62个，其中有42个miRNA在卵巢上皮癌耐药组织中上调、20个miRNA下调，上调miRNA预测到1391个靶基因，下调miRNA预测到1231个靶基因。GO分析结果显示：上调表达的miRNA预测到的靶基因主要参与了细胞蛋白质代谢过程和RNA聚合酶II启动子的转录调控过程，下调表达的miRNA预测的靶基因主要参与转录调控、蛋白酶参与的细胞蛋白质分解代谢过程以及细胞蛋白质分解代谢等过程。KEGG Pathways通路分析提示上调表达的miRNA预测的靶基因主要参与TGF-beta信号通路和粘着连接信号通路。疾病富集分析部分靶基因与卵巢上皮癌或卵巢肿瘤相关。QRT-PCR验证miRNA芯片结果，差异表达的miR-200a-3p、miR-382-5p、miR-1、miR-152和miR-299-5p与芯片表达趋势一致，扩大临床样本验证亦得到了一致的结果，其中miR-200a-3p在卵巢癌耐药组织中下调0.31倍，差异有统计学意义（P＜0.01）；miR-382-5p、miR-152和miR-299-5p分别上调3.53倍、2.69倍和2.70倍，差异有统计学意义（P＜0.01）；miR-1上调1.14倍，差异无统计学意义（P＞0.05）。
结论：我们通过miRNA芯片技术筛选出了跟卵巢上皮癌耐药相关miRNA表达谱，同时靶基因预测提示我们一个miRNA可以调控多个靶基因，而一个靶基因又可能同时受几个miRNA的调控，可见miRNA的调控机理是十分复杂的。生物信息学分析提示差异表达miRNA预测到的靶基因广泛参与多个生物学过程，我们可以推测这些异常表达的miRNA可能通过调控特定功能的靶基因，参与重要信号传导通路，在肿瘤的生长及肿瘤耐药产生过程中发挥重要角色。后期需要进一步研究以认识这些差异miRNA参与卵巢上皮癌耐药发生的相关分子机制。
研究目的：筛选卵巢上皮癌多药耐药相关mRNA表达谱。
材料和方法：采用Agilent lncRNA芯片，检测5例卵巢上皮癌耐药组织、5例敏感组织、5例卵巢良性肿瘤和5例正常卵巢组织的mRNA表达情况，获得与卵巢上皮癌耐药组和敏感组差异大于2倍的上调或下调mRNA。运用GO分析和Pathway通路富集等生物信息学方法分析差异表达mRNA潜在的生物学功能和参与的信号通路。用QRT-PCR验证芯片结果，并扩大样本量检测目的mRNA的表达情况，并分析mRNA表达水平与临床病理因素关系。
结果：mRNA芯片筛选出于卵巢上皮癌多药耐药相关差异表达mRNA共855个，其中在卵巢上皮癌耐药组织中上调表达的mRNA598个，下调表达的257个。生物信息学分析结果显示上调mRNA主要参与细胞粘附、生物黏附、调节细胞增殖、免疫反应以及血管发育等31个生物学过程，下调mRNA未富集到显著相关生物学过程。KEGGPathway分析结果显示上调mRNA主要参与了粘着斑和ECM-受体相互作用的信号传导途径。QRT-PCR验证芯片结果，KIT、HGF、CSF1R、PDGFRB和KIAA1804与芯片表达趋势一致，扩大临床样本验证亦得到了一致的结果，其中KIT、HGF、CSF1R、PDGFRB基因在EOC耐药组织中分别上调3.81倍、2.74、2.03倍和2.92倍，差异有统计学意义（P﹤0.05），而KIAA1804基因则下调0.42倍，差异有统计学意义（P﹤0.05）。
结论：利用基因芯片基础筛选出了跟卵巢上皮癌多药耐药相关的mRNA表达谱，丰富了目前已知的跟耐药相关的靶基因数据。生物信息学提示差异表达mRNA多参与细胞粘附、调节细胞增殖、免疫反应等生物学过程，以及部分mRNA被富集在粘着斑和ECM-受体相互作用的信号通路上，提示这些差异基因可能通过多种途径参与卵巢上皮癌多药耐药的发生，后期需要进一步研究以认识这些差异miRNA参与卵巢上皮癌耐药发生的相关分子机制。
研究目的：构建与卵巢上皮癌多药耐药相关miRNA-mRNA调控网络。
材料和方法：对筛出的卵巢上皮癌多药耐药相关的miRNA差异表达谱和mRNA差异表达谱信息运用MAGIA软件进行整合分析，并选取miRNA跟mRNA负相关的miRNA-mRNA，构建卵巢上皮癌耐药相关miRNA-mRNA调控网络图，并用QRT-PCR方法验证关键位点miRNA和mRNA的表达，并分析miRNA-mRNA表达水平与临床病理因素关系。
结果：miRNA表达谱和mRNA表达谱关联后，共得到53对负关联的miRNA/miRNA，其中包括10个miRNA和43个mRNA，被富集到的靶基因最多的是miR-429和miR-381，对应靶基因数目分别为16个和8个，而被最多miRNA关联调控的mRNA分别是ERBB4、PRKCE和PPP1R9A，印证了一个miRNA调控多个靶基因，而一个靶基因可受到多个miRNA调控。扩大临床样本QRT-PCR验证结果：相比于卵巢癌敏感组，miR-429、miR-373-5p在卵巢耐药组中分别下调0.35倍和0.39倍，差异有统计学意义（P＜0.01）；对应靶基因KANK2、ZEB2和CTSD分别上调2.56倍、3.15倍和1.89倍，差异有统计学意义（P＜0.05）；miR-381、miR-495和miR-410在耐药组中分别上调2.36倍、2.46倍和2.42倍，差异有统计学意义（P＜0.01）；对应的靶基因ERBB4、TIAL1、FGFRL1和MPPED2分别下调0.46倍、0.38倍、0.29倍和0.43倍，差异有统计学意义（P＜0.05）。
结论：经过QRT-PCR验证以及文本挖掘，我们认为构建与卵巢上皮癌多药耐药相关的miRNA-mRNA调控网络图比较可靠，提示了在卵巢癌耐药组织中miRNA和mRNA复杂的调控网络关系，亦从多基因多靶点角度阐述了卵巢上皮癌多药耐药的发生机制。而关键位点的miRNA及其负调控mRNA具体以何种方式和途径参与EOC多药耐药机制的发生，需要后期做进一步深入的功能学研究，以期找到确实可靠的逆转卵巢上皮癌MDR被关键靶点，指导临床更好得防治卵巢上皮癌多药耐药的发生，提高患者预后和生活质量。
Ovarian cancer accounts for third place in the female reproductive tract cancer incidence,but the mortality rate ranks first.Chemotherapy is an important treatment for epithelial ovariancancer(EOC).But multidrug resistance of EOC is a vital link which lead to Chemotherapyfailure. Present study suggests those molecular mechanisms of multidrug resistance of EOCmight involve intracellular chemotherapeutic drug efflux,DNA damage and repair, abnormalMolecular mechanisms of apoptosis and signal transduction pathway disorders. But has yet tofind a safe and effective drug target for reversal multidrug resistance.This study intends todiversify through the use of research tools miRNA microarray technology and gene chiptechnology, and bioinformatics, from clinical studies to basic research and finally returnclinical strategies.Looking for multi-drug resistance molecular mechanism in ovarian cancerfor finding security effective reversal of multidrug resistance.
Objective Construction miRNA exprssion profiles in epithelial ovarian cancer multidrugresistance.
Materials and Methods Using Agilent miRNA chip,detect the miRNAs expressionbetween the five cases of epithelial ovarian cancer tissues with5cases of drug-resistant tissueand5sensitive one,5cases of benign ovarian tumors and5cases of normal ovarian tissue.Ttest and Fc differences was be used to find greater different than2-fold up-regulation ordown-regulation in miRNAs. We mined the data of microRNA-target genes via multiplesonline software.We analysised the target gene of up-regulation or down-regulation miRNAsby GO enrichment analysis and Pathway bioinformatics analysis to predict potential targetgenes and signaling pathways involved in the biological functio. And then we validate themicroarray results using QRT-PCR analysis and expand the sample size to detect theexpression of purpose miRNA.And analyze the relationships between miRNA expressionlevels and clinicopathological factors.
Results A total of62microRNAs expressed differentially related to EOCchemoresistance,there were42miRNAsincreased in ovarian cancer resistance tissue and20ones decreased.And1391target genes were predicted by up-regulation miRNAs,1231targetgenes were predicted by down-regulation miRNAs.GO analysis showed:miRNAs ofup-regulated predicted target genes are involved in regulation of cellular protein metabolicprocess and regulation of transcription from RNA polymerase II promoter.Down-regulateddifferentially predicted target genes are involved in regulation of transcription, proteolysisinvolved in cellular protein catabolic process, cellular protein catabolic process and otherclass of biological process-es.Pathways pathway analysis is enriched to TGF-beta signalingpathway and Adherens junction a signaling pathway for up-regulated predicted target genes.Enrichment for disease analysis showed that part of the target genes associated with epithelialovarian cancer or ovarian cancer.We screened four upregulated genes of miR-382-5p,miR-1,miR-152and miR-299-5p and one down-regulated miR-200a-3p carried by QRT-PCRmicroarray validation. The result matched with the microarray results,expand clinical sampleobtained consistent results,which miR-200a-3p was downregulated0.31-fold in ovariancancer drugresistant tissue via drugsensitive tissue,the difference was statistically significant (P<0.01);miR-382-5p,miR-152and miR-299-5p were raised3.53times,2.69times and2.70times, the differences were statistically significant (P<0.01),miR-1was raised1.14times,butthe difference was not statistically significant (P>0.05).
Conclusion We screened out miRNA expression profiling associated with epithelialovarian cancer multidrug-resistance by miRNA microarray.the result of predicting targetgeneprompted that miRNA can regulate multiple target genes, and a target gene may also beregulated by several of miRNA.Visiblely miRNAregulatory network is very complex.Bioinformatics analysis showed differential expression of miRNA target genes predicted tobroad participation in a number of biological processes,we speculated that these abnormalexpression of miRNA expression is likely through regulatedof target gene take part in cellproliferation and apoptosis related factors,and involved in several signal transductionpathways,may play an important role in tumor growth and cell prognosis.There aesneed forfurther indepth study of these differentially expressed miRNA to identify potential Molecularmechanisms underlying drug resistance in ovarian cancer,as well as clinical diagnosis andtreatment of individual markers, even to effectively reverse the resistance of epithelial ovariancancer treatment provide new ideas.
Objective Construction mRNA exprssion profiles in epithelial ovarian cancer multidrugresistance.
Materials and Methods Using Agilent lncRNA chip,detect themRNAs expressionbetween the five cases of epithelial ovarian cancer group with5cases of drug-resistant tissueand5sensitive one,5cases of benign ovarian tumors and5cases of normal ovarian tissue.Ttest and Fc differences was be used to find greaterdifferent than2-fold up-regulation ordown-regulationin mRNAs.We analysised the target gene of up-regulation or down-regulationmiRNAs by GO enrichment analysis and Pathway bioinformatics analysis to predict thebiological functions and involved inwhich signaling pathways of the differential expression genes. And then we validatethe microarray results using QRT-PCR analysis and expand thesample size to detect the expression of purpose mRNA.And analyze the relationships betweenmiRNA expression levels and clinicopathological factors.
Results A total of855microRNAsexpressed differentially related to EOCchemoresistance,there were598mRNA increased in ovarian cancer resistance tissue and257ones were decreased.Bioinformatics analysis showed that: up-regulation mRNA involved incell adhesion,biological adhesion,regulation of cell prolifera-tion,immune response,bloodvessel development, and other class of biological processes.Down-regulation mRNA is notinvolved in significantly enrichment related biological processes.KEGG Pathway analysisshowed upregulated mRNA related pathways involved in Focal adhesion and ECM-receptorinteraction.We screened four upregulated genes of KIT,HGF,CSF1R,PDGFRB and onedown-regulated ERBB4gene carried by QRT-PCR microarray validation,the results matchedwith the microar-ray results,expand clinical sample obtained consistent results,whichKIT,HGF,CSF1R, PDGFRB genes in EOC drugresistance group were raised3.81times and2.92times2.74,2.03times via drugsensitive group,the difference was statistically significant(P<0.05), while the KIAA1804gene is down-regulated0.42-fold, difference was statisticallysignificance (P<0.05).
Conclusions Microarray-based screening out mRNA expression profiles associated withepithelial ovarian cancer multidrug resistance,which enriching the current data known targetgenes associated with drug resistance.Bioinformatics analysis of the differentially expressedmRNA principalinvolved in cell adhesion,biological adhesion,regulation of cell proliferation,immune response, as well as part of the mRNA is enriched in Focal adhesion and ECM-receptor interaction, suggesting that these differentially expressed genes may be involved inepithelial ovarian cancer multi-drug resistant through a variety of ways.
ObjectiveConstruction miRNA-mRNA regulatory networks associated with epithelialovarian cancer multidrug resistance.
Materials and Methods To screen out the miRNA and mRNA expression profiling ofepithelial ovarian cancer multidrug resistance,we analysised the differences expressionmiRNA and mRNA in expression profiling information using MAGIA meta-analysis software,and select miRNA negatively correlated with mRNA of miRNA/mRNA,build miRNA-mRNAregulatory network diagram associated with epithelial ovarian cancer drug resistance, andverify that the key expression of miRNA and mRNA using QRT-PCR methods.
Results Received a total of53pairs of miRNA-miRNA for negative association,including10miRNA and43mRNA.miR-429and miR-381were enriched by many targetgene, corresponding to the number of target genes was16and8,respectively.The mRNA ofERBB4,PRKCE and PPP1R9A were associated with several miRNA. It was confirmed thatmiRNA regulation a multiple target genes, which gene subject to more than one miRNAregulation. Expanded clinical samples QRT-PCR validation results: compared to ovariancancer sensitive group, miR-429, miR-373-5p in ovarian resistance group were down0.35-fold and0.39-fold,the difference was statistically significant (P<0.01); Thecorresponding target genes KANK2, ZEB2and CTSD were raised2.56times,3.15times and1.89times, the difference was statistically significant (P<0.05); miR-381, miR-495andmiR-410in the drug group were raised2.36times,2.46times and2.42times,the differencewas statistically significant (P<0.01); corresponding target genes ERBB4, TIAL1, FGFRL1and MPPED2were down0.46times,0.38times,0.29times and0.43times, the differencewas statistically significant (P<0.05).
Conclusion After QRT-PCR validation and text mining, we believe that to buildmiRNA-mRNA regulatory network diagram with epithelial ovarian cancer multidrugresistance associated with more reliable.It was display that the miRNA and mRNA complexregulatory network relationshipsin ovarian cancer resistance tissues,also from the perspectiveof multiple genes and multi-targets mechanisms of epithelial ovarian cancer multidrugresistance.The key miRNAand its negative regulation of mRNA in which specific ways andmeans to be involved in multidrug resistance mechanisms EOC, needs to make furtherin-depth functional studiesin order to find a really reliable way that can reversal the epithelialovarian cancer MDR,and happened to better guide clinical Chemical therapy and a effectiveprevention avoid multidrug resistance in ovarian cancer patient,expec-ting improve theprognosis and quality of life for EOC patients.
研究目的：筛选卵巢上皮癌多药耐药相关miRNA表达谱。
材料和方法：采用Agilent miRNA芯片，检测5例卵巢上皮癌耐药组织、5例敏感组织、5例卵巢良性肿瘤和5例正常卵巢组织的miRNA表达情况，运用Fc差异倍数，获得了卵巢上皮癌耐药组和敏感组差异大于2倍的上调或下调miRNA。用多个在线软件分别预测上调和下调差异miRNA对应的靶基因，并运用GO分析和Pathway通路富集等生物信息学方法分析预测到的靶基因潜在的生物学功能和参与的信号通路。用QRT-PCR验证芯片结果，并扩大样本量检测目的miRNA的表达情况，并分析miRNA表达水平与临床病理因素关系。
结果：miRNA芯片筛选出与卵巢上皮癌多药耐药相关的差异表达miRNA共62个，其中有42个miRNA在卵巢上皮癌耐药组织中上调、20个miRNA下调，上调miRNA预测到1391个靶基因，下调miRNA预测到1231个靶基因。GO分析结果显示：上调表达的miRNA预测到的靶基因主要参与了细胞蛋白质代谢过程和RNA聚合酶II启动子的转录调控过程，下调表达的miRNA预测的靶基因主要参与转录调控、蛋白酶参与的细胞蛋白质分解代谢过程以及细胞蛋白质分解代谢等过程。KEGG Pathways通路分析提示上调表达的miRNA预测的靶基因主要参与TGF-beta信号通路和粘着连接信号通路。疾病富集分析部分靶基因与卵巢上皮癌或卵巢肿瘤相关。QRT-PCR验证miRNA芯片结果，差异表达的miR-200a-3p、miR-382-5p、miR-1、miR-152和miR-299-5p与芯片表达趋势一致，扩大临床样本验证亦得到了一致的结果，其中miR-200a-3p在卵巢癌耐药组织中下调0.31倍，差异有统计学意义（P＜0.01）；miR-382-5p、miR-152和miR-299-5p分别上调3.53倍、2.69倍和2.70倍，差异有统计学意义（P＜0.01）；miR-1上调1.14倍，差异无统计学意义（P＞0.05）。
结论：我们通过miRNA芯片技术筛选出了跟卵巢上皮癌耐药相关miRNA表达谱，同时靶基因预测提示我们一个miRNA可以调控多个靶基因，而一个靶基因又可能同时受几个miRNA的调控，可见miRNA的调控机理是十分复杂的。生物信息学分析提示差异表达miRNA预测到的靶基因广泛参与多个生物学过程，我们可以推测这些异常表达的miRNA可能通过调控特定功能的靶基因，参与重要信号传导通路，在肿瘤的生长及肿瘤耐药产生过程中发挥重要角色。后期需要进一步研究以认识这些差异miRNA参与卵巢上皮癌耐药发生的相关分子机制。
研究目的：筛选卵巢上皮癌多药耐药相关mRNA表达谱。
材料和方法：采用Agilent lncRNA芯片，检测5例卵巢上皮癌耐药组织、5例敏感组织、5例卵巢良性肿瘤和5例正常卵巢组织的mRNA表达情况，获得与卵巢上皮癌耐药组和敏感组差异大于2倍的上调或下调mRNA。运用GO分析和Pathway通路富集等生物信息学方法分析差异表达mRNA潜在的生物学功能和参与的信号通路。用QRT-PCR验证芯片结果，并扩大样本量检测目的mRNA的表达情况，并分析mRNA表达水平与临床病理因素关系。
结果：mRNA芯片筛选出于卵巢上皮癌多药耐药相关差异表达mRNA共855个，其中在卵巢上皮癌耐药组织中上调表达的mRNA598个，下调表达的257个。生物信息学分析结果显示上调mRNA主要参与细胞粘附、生物黏附、调节细胞增殖、免疫反应以及血管发育等31个生物学过程，下调mRNA未富集到显著相关生物学过程。KEGGPathway分析结果显示上调mRNA主要参与了粘着斑和ECM-受体相互作用的信号传导途径。QRT-PCR验证芯片结果，KIT、HGF、CSF1R、PDGFRB和KIAA1804与芯片表达趋势一致，扩大临床样本验证亦得到了一致的结果，其中KIT、HGF、CSF1R、PDGFRB基因在EOC耐药组织中分别上调3.81倍、2.74、2.03倍和2.92倍，差异有统计学意义（P﹤0.05），而KIAA1804基因则下调0.42倍，差异有统计学意义（P﹤0.05）。
结论：利用基因芯片基础筛选出了跟卵巢上皮癌多药耐药相关的mRNA表达谱，丰富了目前已知的跟耐药相关的靶基因数据。生物信息学提示差异表达mRNA多参与细胞粘附、调节细胞增殖、免疫反应等生物学过程，以及部分mRNA被富集在粘着斑和ECM-受体相互作用的信号通路上，提示这些差异基因可能通过多种途径参与卵巢上皮癌多药耐药的发生，后期需要进一步研究以认识这些差异miRNA参与卵巢上皮癌耐药发生的相关分子机制。
研究目的：构建与卵巢上皮癌多药耐药相关miRNA-mRNA调控网络。
材料和方法：对筛出的卵巢上皮癌多药耐药相关的miRNA差异表达谱和mRNA差异表达谱信息运用MAGIA软件进行整合分析，并选取miRNA跟mRNA负相关的miRNA-mRNA，构建卵巢上皮癌耐药相关miRNA-mRNA调控网络图，并用QRT-PCR方法验证关键位点miRNA和mRNA的表达，并分析miRNA-mRNA表达水平与临床病理因素关系。
结果：miRNA表达谱和mRNA表达谱关联后，共得到53对负关联的miRNA/miRNA，其中包括10个miRNA和43个mRNA，被富集到的靶基因最多的是miR-429和miR-381，对应靶基因数目分别为16个和8个，而被最多miRNA关联调控的mRNA分别是ERBB4、PRKCE和PPP1R9A，印证了一个miRNA调控多个靶基因，而一个靶基因可受到多个miRNA调控。扩大临床样本QRT-PCR验证结果：相比于卵巢癌敏感组，miR-429、miR-373-5p在卵巢耐药组中分别下调0.35倍和0.39倍，差异有统计学意义（P＜0.01）；对应靶基因KANK2、ZEB2和CTSD分别上调2.56倍、3.15倍和1.89倍，差异有统计学意义（P＜0.05）；miR-381、miR-495和miR-410在耐药组中分别上调2.36倍、2.46倍和2.42倍，差异有统计学意义（P＜0.01）；对应的靶基因ERBB4、TIAL1、FGFRL1和MPPED2分别下调0.46倍、0.38倍、0.29倍和0.43倍，差异有统计学意义（P＜0.05）。
结论：经过QRT-PCR验证以及文本挖掘，我们认为构建与卵巢上皮癌多药耐药相关的miRNA-mRNA调控网络图比较可靠，提示了在卵巢癌耐药组织中miRNA和mRNA复杂的调控网络关系，亦从多基因多靶点角度阐述了卵巢上皮癌多药耐药的发生机制。而关键位点的miRNA及其负调控mRNA具体以何种方式和途径参与EOC多药耐药机制的发生，需要后期做进一步深入的功能学研究，以期找到确实可靠的逆转卵巢上皮癌MDR被关键靶点，指导临床更好得防治卵巢上皮癌多药耐药的发生，提高患者预后和生活质量。
Ovarian cancer accounts for third place in the female reproductive tract cancer incidence,but the mortality rate ranks first.Chemotherapy is an important treatment for epithelial ovariancancer(EOC).But multidrug resistance of EOC is a vital link which lead to Chemotherapyfailure. Present study suggests those molecular mechanisms of multidrug resistance of EOCmight involve intracellular chemotherapeutic drug efflux,DNA damage and repair, abnormalMolecular mechanisms of apoptosis and signal transduction pathway disorders. But has yet tofind a safe and effective drug target for reversal multidrug resistance.This study intends todiversify through the use of research tools miRNA microarray technology and gene chiptechnology, and bioinformatics, from clinical studies to basic research and finally returnclinical strategies.Looking for multi-drug resistance molecular mechanism in ovarian cancerfor finding security effective reversal of multidrug resistance.
Objective Construction miRNA exprssion profiles in epithelial ovarian cancer multidrugresistance.
Materials and Methods Using Agilent miRNA chip,detect the miRNAs expressionbetween the five cases of epithelial ovarian cancer tissues with5cases of drug-resistant tissueand5sensitive one,5cases of benign ovarian tumors and5cases of normal ovarian tissue.Ttest and Fc differences was be used to find greater different than2-fold up-regulation ordown-regulation in miRNAs. We mined the data of microRNA-target genes via multiplesonline software.We analysised the target gene of up-regulation or down-regulation miRNAsby GO enrichment analysis and Pathway bioinformatics analysis to predict potential targetgenes and signaling pathways involved in the biological functio. And then we validate themicroarray results using QRT-PCR analysis and expand the sample size to detect theexpression of purpose miRNA.And analyze the relationships between miRNA expressionlevels and clinicopathological factors.
Results A total of62microRNAs expressed differentially related to EOCchemoresistance,there were42miRNAsincreased in ovarian cancer resistance tissue and20ones decreased.And1391target genes were predicted by up-regulation miRNAs,1231targetgenes were predicted by down-regulation miRNAs.GO analysis showed:miRNAs ofup-regulated predicted target genes are involved in regulation of cellular protein metabolicprocess and regulation of transcription from RNA polymerase II promoter.Down-regulateddifferentially predicted target genes are involved in regulation of transcription, proteolysisinvolved in cellular protein catabolic process, cellular protein catabolic process and otherclass of biological process-es.Pathways pathway analysis is enriched to TGF-beta signalingpathway and Adherens junction a signaling pathway for up-regulated predicted target genes.Enrichment for disease analysis showed that part of the target genes associated with epithelialovarian cancer or ovarian cancer.We screened four upregulated genes of miR-382-5p,miR-1,miR-152and miR-299-5p and one down-regulated miR-200a-3p carried by QRT-PCRmicroarray validation. The result matched with the microarray results,expand clinical sampleobtained consistent results,which miR-200a-3p was downregulated0.31-fold in ovariancancer drugresistant tissue via drugsensitive tissue,the difference was statistically significant (P<0.01);miR-382-5p,miR-152and miR-299-5p were raised3.53times,2.69times and2.70times, the differences were statistically significant (P<0.01),miR-1was raised1.14times,butthe difference was not statistically significant (P>0.05).
Conclusion We screened out miRNA expression profiling associated with epithelialovarian cancer multidrug-resistance by miRNA microarray.the result of predicting targetgeneprompted that miRNA can regulate multiple target genes, and a target gene may also beregulated by several of miRNA.Visiblely miRNAregulatory network is very complex.Bioinformatics analysis showed differential expression of miRNA target genes predicted tobroad participation in a number of biological processes,we speculated that these abnormalexpression of miRNA expression is likely through regulatedof target gene take part in cellproliferation and apoptosis related factors,and involved in several signal transductionpathways,may play an important role in tumor growth and cell prognosis.There aesneed forfurther indepth study of these differentially expressed miRNA to identify potential Molecularmechanisms underlying drug resistance in ovarian cancer,as well as clinical diagnosis andtreatment of individual markers, even to effectively reverse the resistance of epithelial ovariancancer treatment provide new ideas.
Objective Construction mRNA exprssion profiles in epithelial ovarian cancer multidrugresistance.
Materials and Methods Using Agilent lncRNA chip,detect themRNAs expressionbetween the five cases of epithelial ovarian cancer group with5cases of drug-resistant tissueand5sensitive one,5cases of benign ovarian tumors and5cases of normal ovarian tissue.Ttest and Fc differences was be used to find greaterdifferent than2-fold up-regulation ordown-regulationin mRNAs.We analysised the target gene of up-regulation or down-regulationmiRNAs by GO enrichment analysis and Pathway bioinformatics analysis to predict thebiological functions and involved inwhich signaling pathways of the differential expression genes. And then we validatethe microarray results using QRT-PCR analysis and expand thesample size to detect the expression of purpose mRNA.And analyze the relationships betweenmiRNA expression levels and clinicopathological factors.
Results A total of855microRNAsexpressed differentially related to EOCchemoresistance,there were598mRNA increased in ovarian cancer resistance tissue and257ones were decreased.Bioinformatics analysis showed that: up-regulation mRNA involved incell adhesion,biological adhesion,regulation of cell prolifera-tion,immune response,bloodvessel development, and other class of biological processes.Down-regulation mRNA is notinvolved in significantly enrichment related biological processes.KEGG Pathway analysisshowed upregulated mRNA related pathways involved in Focal adhesion and ECM-receptorinteraction.We screened four upregulated genes of KIT,HGF,CSF1R,PDGFRB and onedown-regulated ERBB4gene carried by QRT-PCR microarray validation,the results matchedwith the microar-ray results,expand clinical sample obtained consistent results,whichKIT,HGF,CSF1R, PDGFRB genes in EOC drugresistance group were raised3.81times and2.92times2.74,2.03times via drugsensitive group,the difference was statistically significant(P<0.05), while the KIAA1804gene is down-regulated0.42-fold, difference was statisticallysignificance (P<0.05).
Conclusions Microarray-based screening out mRNA expression profiles associated withepithelial ovarian cancer multidrug resistance,which enriching the current data known targetgenes associated with drug resistance.Bioinformatics analysis of the differentially expressedmRNA principalinvolved in cell adhesion,biological adhesion,regulation of cell proliferation,immune response, as well as part of the mRNA is enriched in Focal adhesion and ECM-receptor interaction, suggesting that these differentially expressed genes may be involved inepithelial ovarian cancer multi-drug resistant through a variety of ways.
ObjectiveConstruction miRNA-mRNA regulatory networks associated with epithelialovarian cancer multidrug resistance.
Materials and Methods To screen out the miRNA and mRNA expression profiling ofepithelial ovarian cancer multidrug resistance,we analysised the differences expressionmiRNA and mRNA in expression profiling information using MAGIA meta-analysis software,and select miRNA negatively correlated with mRNA of miRNA/mRNA,build miRNA-mRNAregulatory network diagram associated with epithelial ovarian cancer drug resistance, andverify that the key expression of miRNA and mRNA using QRT-PCR methods.
Results Received a total of53pairs of miRNA-miRNA for negative association,including10miRNA and43mRNA.miR-429and miR-381were enriched by many targetgene, corresponding to the number of target genes was16and8,respectively.The mRNA ofERBB4,PRKCE and PPP1R9A were associated with several miRNA. It was confirmed thatmiRNA regulation a multiple target genes, which gene subject to more than one miRNAregulation. Expanded clinical samples QRT-PCR validation results: compared to ovariancancer sensitive group, miR-429, miR-373-5p in ovarian resistance group were down0.35-fold and0.39-fold,the difference was statistically significant (P<0.01); Thecorresponding target genes KANK2, ZEB2and CTSD were raised2.56times,3.15times and1.89times, the difference was statistically significant (P<0.05); miR-381, miR-495andmiR-410in the drug group were raised2.36times,2.46times and2.42times,the differencewas statistically significant (P<0.01); corresponding target genes ERBB4, TIAL1, FGFRL1and MPPED2were down0.46times,0.38times,0.29times and0.43times, the differencewas statistically significant (P<0.05).
Conclusion After QRT-PCR validation and text mining, we believe that to buildmiRNA-mRNA regulatory network diagram with epithelial ovarian cancer multidrugresistance associated with more reliable.It was display that the miRNA and mRNA complexregulatory network relationshipsin ovarian cancer resistance tissues,also from the perspectiveof multiple genes and multi-targets mechanisms of epithelial ovarian cancer multidrugresistance.The key miRNAand its negative regulation of mRNA in which specific ways andmeans to be involved in multidrug resistance mechanisms EOC, needs to make furtherin-depth functional studiesin order to find a really reliable way that can reversal the epithelialovarian cancer MDR,and happened to better guide clinical Chemical therapy and a effectiveprevention avoid multidrug resistance in ovarian cancer patient,expec-ting improve theprognosis and quality of life for EOC patients.
引文
[1]Banerjee S. and Kaye S. B.New strategies in the treatment of ovarian cancer: currentclinical perspectives and future potential[J].Clin Cancer Res.2013,19(5):961-8.
[2]Jemal A.,Siegel R.,Xu J., et al.Cancer statistics,2010[J].CA Cancer J Clin.2010,60(5):277-300.
[3]Siegel R.,Naishadham D. and Jemal A.Cancer statistics,2012[J].CA Cancer J Clin.2012,62(1):10-29.
[4]Samrao D.,Wang D.,Ough F.,et al.Histologic parameters predictive of diseaseoutcome in women with advanced stage ovarian carcinoma treated with neoadjuvantchemotherapy[J]. Transl Oncol.2012,5(6):469-74.
[5]Matsuo K.,Eno M. L.,Im D. D., et al.Clinical relevance of extent of extreme drugresistance in epithelial ovarian carcinoma[J].Gynecol Oncol.2010,116(1):61-5.
[6] National Comprehensive Cancer Network: The NCCN clinical practice guidelines inoncology ovarian cancer(version1).[J]2014.
[7]du Bois A.,Luck H. J.,Meier W., et al.A randomized clinical trial ofcisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer[J].JNatl Cancer Inst.2003,95(17):1320-9.
[8]Katsumata N.,Yasuda M.,Takahashi F., et al.Dose-dense paclitaxel once a week incombination with carboplatin every3weeks for advanced ovarian cancer: a phase3,open-label, randomised controlled trial[J].Lancet.2009,374(9698):1331-8.
[9]Pignata S.,Scambia G.,Katsaros D., et al.Carboplatin plus paclitaxel once a weekversus every3weeks in patients with advanced ovarian cancer (MITO-7): a randomised,multicentre, open-label, phase3trial[J].Lancet Oncol.2014,15(4):396-405.
[10]Kumagai M.,Fujii T.,Komatsu M., et al.Paclitaxel plus carboplatin in ovariancancer-comparison of adverse effects between monthly and weekly administration[J].Gan ToKagaku Ryoho.2004,31(4):555-9.
[11]Katsumata N.,Yasuda M.,Isonishi S., et al.Long-term results of dose-dense paclitaxeland carboplatin versus conventional paclitaxel and carboplatin for treatment of advancedepithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG3016): a randomised,controlled, open-label trial[J].Lancet Oncol.2013,14(10):1020-6.
[12]Piccart M. J.,Du Bois A.,Gore M. E., et al.A new standard of care for treatment ofovarian cancer[J].Eur J Cancer.2000,36(1):10-2.
[13]Winter-Roach B. A.,Kitchener H. C. and Lawrie T. A.Adjuvant (post-surgery)chemotherapy for early stage epithelial ovarian cancer[J].Cochrane Database SystRev.2012,3(CD004706).
[14]Lawrie T. A.,Rabbie R.,Thoma C., et al.Pegylated liposomal doxorubicin forfirst-line treatment of epithelial ovarian cancer[J].Cochrane Database Syst Rev.2013,10(CD010482).
[15]Staropoli N.,Ciliberto D.,Botta C., et al.Pegylated liposomal doxorubicin in themanagement of ovarian cancer: A systematic review and metaanalysis of randomizedtrials[J].Cancer Biol Ther.2014,15(6):707-20.
[16]Heintz AP O. F., Maisonneuve P,et al.FIGO (International Federation of Gynecologyand Obstetrics)26th Annual Report on the Results of Treatment in GynecologicalCancer[J].Int J Gynaecol Obstet.2006,95Suppl1(S1-257).
[17]Gadducci A.,Cosio S.,Zola P., et al.Prognostic factors and clinical outcome ofpatients with recurrent early-stage epithelial ovarian cancer: an Italian multicenterretrospective study[J].Int J Gynecol Cancer.2013,23(3):461-8.
[18]Winter W. E.,3rd,Maxwell G. L.,Tian C., et al.Prognostic factors for stage IIIepithelial ovarian cancer: a Gynecologic Oncology Group Study[J].J Clin Oncol.2007,25(24):3621-7.
[19]Fu Y.,Wang X.,Pan Z., et al.Clinical outcomes and prognostic factors of patients withepithelial ovarian cancer subjected to first-line treatment: a retrospective study of251cases[J].Front Med.2014,8(1):91-5.
[20]Mackay H. J.,Brady M. F.,Oza A. M., et al.Prognostic relevance of uncommonovarian histology in women with stage III/IV epithelial ovarian cancer[J].Int J GynecolCancer.2010,20(6):945-52.
[21]Gershenson D. M.,Sun C. C.,Lu K. H., et al.Clinical behavior of stage II-IVlow-grade serous carcinoma of the ovary[J].Obstet Gynecol.2006,108(2):361-8.
[22]Bosari S.,Viale G.,Radaelli U., et al.p53accumulation in ovarian carcinomas and itsprognostic implications[J].Hum Pathol.1993,24(11):1175-9.
[23]Kowalski L.D.,Kanbour A.I.,Price F.V.,et al.A case-matched molecular comparisonof extraovarian versus primary ovarian adenocarcinoma[J].Cancer.1997,79(8):1587-94.
[24]Skirnisdottir I. and Sorbe B.Prognostic factors for surgical outcome and survival in447women treated for advanced (FIGO-stages III-IV) epithelial ovarian carcinoma[J].Int JOncol.2007,30(3):727-34.
[25]林仲秋,李晶.妇科肿瘤学原理与实践(第5版),北京:[J].人民卫生出版社.2012,900.
[26]Marusyk A.,Almendro V. and Polyak K.Intra-tumour heterogeneity: a looking glassfor cancer[J].Nat Rev Cancer.2012,12(5):323-34.
[27]Khalique L.,Ayhan A.,Weale M. E., et al.Genetic intra-tumour heterogeneity inepithelial ovarian cancer and its implications for molecular diagnosis of tumours[J].JPathol.2007,211(3):286-95.
[28]Cooke S. L.,Ng C. K.,Melnyk N., et al.Genomic analysis of genetic heterogeneityand evolution in high-grade serous ovarian carcinoma[J].Oncogene.2010,29(35):4905-13.
[29]Baba T.,Convery P. A.,Matsumura N., et al.Epigenetic regulation of CD133andtumorigenicity of CD133+ovarian cancer cells[J].Oncogene.2009,28(2):209-18.
[30]Bar J. K.,Harlozinska A.,Popiela A., et al.Expression and mutation of p53in tumoreffusion cells of patients with ovarian carcinoma: response to cisplatin-based chemotherapy[J].Tumour Biol.2001,22(2):83-91.
[31]Rubin S. C.Chemoprevention of hereditary ovarian cancer[J].N Engl J Med.1998,339(7):469-71.
[32]Peng C.,Zhang X.,Yu H.,et al.Wnt5a as a predictor in poor clinical outcome ofpatients and a mediator in chemoresistance of ovarian cancer[J].Int J Gynecol Cancer.2011,21(2):280-8.
[33]Chien J. R.,Aletti G.,Bell D. A.,et al.Molecular pathogenesis and therapeutic targetsin epithelial ovarian cancer[J].J Cell Biochem.2007,102(5):1117-29.
[34]Kurman R. J. and Shih Ie M.The origin and pathogenesis of epithelial ovarian cancer:a proposed unifying theory[J].Am J Surg Pathol.2010,34(3):433-43.
[35]Cheng E. J.,Kurman R. J.,Wang M., et al.Molecular genetic analysis of ovarianserous cystadenomas [J].Lab Invest.2004,84(6):778-84.
[36]Shih Ie M. and Kurman R. J.Ovarian tumorigenesis: a proposed model based onmorphological and molecular genetic analysis[J].Am J Pathol.2004,164(5):1511-8.
[37]Salani R.,Kurman R. J.,Giuntoli R.,2nd, et al.Assessment of TP53mutation usingpurified tissue samples of ovarian serous carcinomas reveals a higher mutation rate thanpreviously reported and does not correlate with drug resistance[J].Int J GynecolCancer.2008,18(3):487-91.
[38]Malpica A.,Deavers M. T.,Lu K., et al.Grading ovarian serous carcinoma using atwo-tier system[J].Am J Surg Pathol.2004,28(4):496-504.
[39]Calatozzolo C.,Gelati M.,Ciusani E., et al.Expression of drug resistance proteins Pgp,MRP1, MRP3, MRP5and GST-pi in human glioma[J].J Neurooncol.2005,74(2):113-21.
[40]Yakirevich E.,Sabo E.,Naroditsky I., et al.Multidrug resistance-related phenotypeand apoptosis-related protein expression in ovarian serous carcinomas[J].Gynecol Oncol.2006,100(1):152-9.
[41]Loo T. W. and Clarke D. M.Mutational analysis of ABC proteins[J].Arch BiochemBiophys.2008,476(1):51-64.
[42]Wu C. P.,Hsieh C. H. and Wu Y. S.The emergence of drug transporter-mediatedmultidrug resistance to cancer chemotherapy[J].Mol Pharm.2011,8(6):1996-2011.
[43]Sharom F. J.The P-glycoprotein multidrug transporter[J].Essays Biochem.2011,50(1):161-78.
[44]Holzmayer T. A.,Hilsenbeck S.,Von Hoff D. D., et al.Clinical correlates of MDR1(P-glycoprotein) gene expression in ovarian and small-cell lung carcinomas[J].J Natl CancerInst.1992,84(19):1486-91.
[45]Han xiaohon G. x., Xue yanjian.On cancer multidrugresistance reversal[J].Journal ofBei Hua University.2005,6(1):36-37.
[46]Kavallaris M.,Leary J.A.,Barrett J.A.,et al.MDR1and multidrug resistance-associated protein (MRP) gene expression in epithelial ovarian tumors[J].Cancer Lett.1996,102(1-2):7-16.
[47]Zhu H.,Wu H.,Liu X., et al.Role of MicroRNA miR-27a and miR-451in theregulation of MDR1/P-glycoprotein expression in human cancer cells[J].Biochem Phar-macol.2008,76(5):582-8.
[48]Lu L.,Katsaros D.,Wiley A., et al.Expression of MDR1in epithelial ovarian cancerand its association with disease progression[J].Oncol Res.2007,16(8):395-403.
[49]Chen H.,Hao J.,Wang L., et al.Coexpression of invasive markers (uPA, CD44) andmultiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancerprogression[J].Br J Cancer.2009,101(3):432-40.
[50]Munoz M.,Henderson M.,Haber M., et al.Role of the MRP1/ABCC1multidrugtransporter protein in cancer[J].IUBMB Life.2007,59(12):752-7.
[51]Kuo T. H.,Liu F. Y.,Chuang C. Y., et al.To predict response chemotherapy usingtechnetium-99m tetrofosmin chest images in patients with untreated small cell lung cancerand compare with p-glycoprotein, multidrug resistance related protein-1, and lungresistance-related protein expression[J].Nucl Med Biol.2003,30(6):627-32.
[52]Yeh J. J.,Hsu N. Y.,Hsu W. H., et al.Comparison of chemotherapy response withP-glycoprotein, multidrug resistance-related protein-1, and lung resistance-related proteinexpression in untreated small cell lung cancer[J].Lung.2005,183(3):177-83.
[53]Ohishi Y.,Oda Y.,Uchiumi T., et al.ATP-binding cassette superfamily transportergene expression in human primary ovarian carcinoma[J].Clin Cancer Res.2002,8(12):3767-75.
[54]Horvath V.,Blanarova O.,Svihalkova-Sindlerova L., et al.Platinum(IV) complex withadamantylamine overcomes intrinsic resistance to cisplatin in ovarian cancer cells[J].GynecolOncol.2006,102(1):32-40.
[55]Ni Z.,Bikadi Z.,Rosenberg M. F., et al.Structure and function of the human breastcancer resistance protein (BCRP/ABCG2)[J].Curr Drug Metab.2010,11(7):603-17.
[56]Lage H. and Dietel M.Effect of the breast-cancer resistance protein on atypicalmultidrug resistance [J].Lancet Oncol.2000,1:169-75.
[57]Ejendal K. F. and Hrycyna C. A.Multidrug resistance and cancer: the role of thehuman ABC transporter ABCG2[J].Curr Protein Pept Sci.2002,3(5):503-11.
[58]Kanzaki A.,Toi M.,Nakayama K., et al.Expression of multidrug resistance-relatedtransporters in human breast carcinoma[J].Jpn J Cancer Res.2001,92(4):452-8.
[59]Maliepaard M.,van Gastelen M. A.,de Jong L. A., et al.Overexpression of theBCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line[J].Cancer Res.1999,59(18):4559-63.
[60]Beeghly A.,Katsaros D.,Chen H., et al.Glutathione S-transferase polymorphisms andovarian cancer treatment and survival[J].Gynecol Oncol.2006,100(2):330-7.
[61]Todo Y.Analysis of p53, MDR-1, and GST-pi expression in endometrialcarcinoma[J].Hokkaido Igaku Zasshi.2003,78(2):117-27.
[62]Cao D. Y.,Shen K.,Yang J. X., et al.The expression of MRP, GST-pi, Topo IIalphaand COX-2in epithelial ovarian cancer and its relationship to drug resistance andprognosis[J].Zhonghua Yi Xue Za Zhi.2007,87(25):1738-41.
[63]Kang S.,Sun H. Y.,Zhou R. M., et al.DNA repair gene associated with clinicaloutcome of epithelial ovarian cancer treated with platinum-based chemotherapy[J].Asian PacJ Cancer Prev.2013,14(2):941-6.
[64]Moxley K. M.,Benbrook D. M.,Queimado L., et al.The role of single nucleotidepolymorphisms of the ERCC1and MMS19genes in predicting platinum-sensitivity,progression-free and overall survival in advanced epithelial ovarian cancer[J].GynecolOncol.2013,130(2):377-82.
[65]Helleman J.,van Staveren I. L.,Dinjens W. N., et al.Mismatch repair and treatmentresistance in ovarian cancer[J].BMC Cancer.2006,6(201).
[66]Scartozzi M.,De Nictolis M.,Galizia E., et al.Loss of hMLH1expression correlateswith improved survival in stage III-IV ovarian cancer patients[J].Eur J Cancer.2003,39(8):1144-9.
[67]Chetrit A.,Hirsh-Yechezkel G.,Ben-David Y., et al.Effect of BRCA1/2mutations onlong-term survival of patients with invasive ovarian cancer: the national Israeli study ofovarian cancer[J].J Clin Oncol.2008,26(1):20-5.
[68]Gourley C.,Michie C. O.,Roxburgh P., et al.Increased incidence of visceralmetastases in scottish patients with BRCA1/2-defective ovarian cancer: an extension of theovarian BRCAness phenotype[J].J Clin Oncol.2010,28(15):2505-11.
[69]Lee S.,Choi E. J.,Jin C., et al.Activation of PI3K/Akt pathway by PTEN reductionand PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cellline[J].Gynecol Oncol.2005,97(1):26-34.
[70]Fraser M.,Leung B. M.,Yan X., et al.p53is a determinant of X-linked inhibitor ofapoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells[J].CancerRes.2003,63(21):7081-8.
[71]Yang J. M.,Vassil A. D. and Hait W. N.Activation of phospholipase C induces theexpression of the multidrug resistance (MDR1) gene through the Raf-MAPK pathway[J].MolPharmacol.2001,60(4):674-80.
[72]焦今文,王蕾,温放等.p38MAPK在不同化疗后卵巢癌中的表达及临床意义[J].中国现代医学杂志.2011,21(15):1828.
[73]Fujita T.,Washio K.,Takabatake D., et al.Proteasome inhibitors can alter the signalingpathways and attenuate the P-glycoprotein-mediated multidrug resistance[J].Int J Cancer.2005,117(4):670-82.
[74]Mackay H. J. and Twelves C. J.Protein kinase C: a target for anticancer drugs[J].Endocr Relat Cancer.2003,10(3):389-96.
[75]卢丹,王志学.卵巢癌组织中多药耐药基因蛋白表达及其临床价值[J].肿瘤防治研究.2004,5:512-514.
[76]金晶,吴绪峰,陈惠祯.P-gp、PKC-α和MRP在上皮性卵巢癌中的表达及其临床意义[J].现代肿瘤医学.2006,14(3):325-329.
[77]Chakrabarty S. and Huang S.Modulation of chemosensitivity in human coloncarcinoma cells by downregulating protein kinase C alpha expression[J].J Exp TherOncol.1996,1(4):218-21.
[78]Masanek U.,Stammler G. and Volm M.Modulation of multidrug resistance in humanovarian cancer cell lines by inhibition of P-glycoprotein170and PKC isoenzymes withantisense oligonucleotides[J].J Exp Ther Oncol.2002,2(1):37-41.
[79]Koti M.,Gooding R. J.,Nuin P., et al.Identification of the IGF1/PI3K/NFkappaB/ERK gene signalling networks associated with chemotherapy resistance andtreatment response in high-grade serous epithelial ovarian cancer[J].BMC Cancer.2013,13:549.
[80]Hung C. C. and Liou H. H.YC-1, a novel potential anticancer agent, inhibitmultidrug-resistant protein via cGMP-dependent pathway[J].Invest New Drugs.2011,29(6):1337-46.
[81]Cao C.,Lu S.,Sowa A., et al.Priming with EGFR tyrosine kinase inhibitor and EGFsensitizes ovarian cancer cells to respond to chemotherapeutical drugs[J].Cancer Lett.2008,266(2):249-62.
[82]L'Esperance S.,Popa I.,Bachvarova M., et al.Gene expression profiling of pairedovarian tumors obtained prior to and following adjuvant chemotherapy: molecular signaturesof chemoresistant tumors[J].Int J Oncol.2006,29(1):5-24.
[83]Chmelarova M.,Krepinska E.,Spacek J., et al.Methylation in the p53promoter inepithelial ovarian cancer[J].Clin Transl Oncol.2013,15(2):160-3.
[84]Kobayashi N.,Abedini M.,Sakuragi N., et al.PRIMA-1increases cisplatin sensitivityin chemoresistant ovarian cancer cells with p53mutation: a requirement for Akt down-regulation[J].J Ovarian Res.2013,6(1):7.
[85]Yang X.,Fraser M.,Moll U. M., et al.Akt-mediated cisplatin resistance in ovariancancer:modulation of p53action on caspase-dependent mitochondrial death pathway[J].Cancer Res.2006,66(6):3126-36.
[86]Materna V.,Surowiak P.,Markwitz E., et al.Expression of factors involved inregulation of DNA mismatch repair-and apoptosis pathways in ovarian cancer patients[J].Oncol Rep.2007,17(3):505-16.
[87]Wang Y. L.,Yan Y. L.,Zhou N. J., et al.Mechanism of multidrug resistance of humansmall cell lung cancer cell line H446/VP[J].Chin Med J (Engl).2010,123(22):3299-303.
[88]Ryan B. M.,O'Donovan N. and Duffy M. J.Survivin: a new target for anti-cancertherapy[J].Cancer Treat Rev.2009,35(7):553-62.
[89]Jiang L.,Luo R. Y.,Yang J., et al.Knockdown of survivin contributes to antitumoractivity in cisplatin-resistant ovarian cancer cells[J].Mol Med Rep.2013,7(2):425-30.
[90]Park S. J.,Armstrong S.,Kim C. H., et al.Lack of EGF receptor contributes to drugsensitivity of human germline cells[J].Br J Cancer.2005,92(2):334-41.
[91]Surowiak P.,Materna V.,Maciejczyk A., et al.Nuclear metallothionein expressioncorrelates with cisplatin resistance of ovarian cancer cells and poor clinical outcome[J].Virchows Arch.2007,450(3):279-85.
[92]Rangel L. B.,Agarwal R.,D'Souza T., et al.Tight junction proteins claudin-3andclaudin-4are frequently overexpressed in ovarian cancer but not in ovariancystadenomas[J].Clin Cancer Res.2003,9(7):2567-75.
[93]Negura L.,Uhrhammer N.,Negura A., et al.Complete BRCA mutation screening inbreast and ovarian cancer predisposition families from a North-Eastern Romanianpopulation[J].Fam Cancer.2010,9(4):519-23.
[94]Pruthi S.,Gostout B. S. and Lindor N. M.Identification and Management of WomenWith BRCA Mutations or Hereditary Predisposition for Breast and Ovarian Cancer[J].MayoClin Proc.2010,85(12):1111-20.
[95]Gallagher D. J.,Konner J. A.,Bell-McGuinn K. M., et al.Survival in epithelialovarian cancer: a multivariate analysis incorporating BRCA mutation status and platinumsensitivity[J].Ann Oncol.2011,22(5):1127-32.
[96]Xu M.,Shao J. and Zeng Y.Molecular classification and molecular targeted therapyof cancer[J].Front Med.2013,7(2):147-9.
[97]Sood A. K. and Buller R. E.Drug resistance in ovarian cancer: from the laboratory tothe clinic[J].Obstet Gynecol.1998,92(2):312-9.
[98]van der Pol M. A.,Broxterman H. J.,Pater J. M., et al.Function of the ABCtransporters, P-glycoprotein, multidrug resistance protein and breast cancer resistance protein,in minimal residual disease in acute myeloid leukemia[J].Haematologica.2003,88(2):134-47.
[99]李晶,吴妙芳,林仲秋.2012NCCN卵巢癌包括输卵管癌和原发腹膜癌临床实践指南（第二版）解读（续）—上皮性卵巢癌[J].国际妇产科学杂志.2012,39(2):315-318.
[100]赵晓东,张毅,杨丽等.复发性卵巢上皮癌"常规化疗药物疗效预测分子靶向化疗"的初步探讨[J].现代妇产科进展.2006,15(4):265-8.
[101]赵晓东,张毅.常规化疗药物疗效预测分子与化疗选药[J].癌症.2006,25(12):1577-80.
[102]Selvakumaran M.,Pisarcik D. A.,Bao R., et al.Enhanced cisplatin cytotoxicity bydisturbing the nucleo-tide excision repair pathway in ovarian cancer cell lines[J].CancerRes.2003,63(6):1311-6.
[103]彭玮丹,张杰,赵永同等.bcl-2核酶(Ribozyme)促进紫杉醇诱导的细胞凋亡[J].中国生物化学与分子生物学报.2000,16(2):258-263.
[104]Zhang T.,Guan M.,Jin H. Y., et al.Reversal of multidrug resistance by smallinterfering double-stranded RNAs in ovarian cancer cells[J].Gynecol Oncol.2005,97(2):501-7.
[105]Rein D. T.,Volkmer A.,Bauerschmitz G., et al.Combination of a MDR1-targetedreplicative adenovirus and chemotherapy for the therapy of pretreated ovarian cancer[J].JCancer Res Clin Oncol.2012,138(4):603-10.
[106]Buller R. E.,Runnebaum I. B.,Karlan B. Y., et al.A phase I/II trial of rAd/p53(SCH58500) gene replacement in recurrent ovarian cancer[J].Cancer Gene Ther.2002,9(7):553-66.
[107]Kumaran G. C.,Jayson G. C. and Clamp A. R.Antiangiogenic drugs in ovariancancer[J].Br J Cancer.2009,100(1):1-7.
[108]Burger R. A.,Sill M. W.,Monk B. J., et al.Phase II trial of bevacizumab in persistentor recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic OncologyGroup Study[J].J Clin Oncol.2007,25(33):5165-71.
[109]Pujade-Lauraine E.,Hilpert F.,Weber B., et al.Bevacizumab Combined WithChemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: The AURELIA Open-LabelRandomized Phase III Trial[J].J Clin Oncol.2014,32(13):1302-8.
[110]Kataria T.,Gupta D.,Bisht S. S., et al.Adaptive Radiotherapy in Lung Cancer:Dosimetric benefits and Clinical outcome[J].Br J Radiol.2014,20130643.
[111]Matei D.,Sill M. W.,Lankes H. A., et al.Activity of sorafenib in recurrent ovariancancer and primary peritoneal carcinomatosis: a gynecologic oncology group trial[J].J ClinOncol.2011,29(1):69-75.
[112]Langdon S. P.,Faratian D.,Nagumo Y., et al.Pertuzumab for the treatment of ovariancancer[J].Expert Opin Biol Ther.2010,10(7):1113-20.
[113]Pautier P.,Joly F.,Kerbrat P., et al.Phase II study of gefitinib in combination withpaclitaxel (P) and carboplatin (C) as second-line therapy for ovarian, tubal or peritonealadenocarcinoma (1839IL/0074)[J].Gynecol Oncol.2010,116(2):157-62.
[114]李蕴潜,赵丽艳,李才.选择性靶向肿瘤干细胞药物的研究现状[J].中国新药杂志.2013,22(24):2903-08.
[115]Schena M.,Shalon D.,Davis R. W., et al.Quantitative monitoring of gene expressionpatterns with a complementary DNA microarray[J].Science.1995,270(5235):467-70.
[116]McCormick M. L.,Gavrila D. and Weintraub N. L.Role of oxidative stress in thepathogenesis of abdominal aortic aneurysms[J].Arterioscler Thromb Vasc Biol.2007,27(3):461-9.
[117]Marchese E.,Vignati A.,Albanese A., et al.Comparative evaluation of genome-widegene expression profiles in ruptured and unruptured human intracranial aneurysms[J].J BiolRegul Homeost Agents.2010,24(2):185-95.
[118]Heller M. J.DNA microarray technology: devices, systems, and applications[J].Annu Rev Biomed Eng.2002,4:129-53.
[119]Subramanian A.,Tamayo P.,Mootha V. K., et al.Gene set enrichment analysis: aknowledge-based approach for interpreting genome-wide expression profiles[J].Proc NatlAcad Sci U S A.2005,102(43):15545-50.
[120]Liu Q.,Dinu I.,Adewale A. J., et al.Comparative evaluation of gene-set analysismethods[J].BMC Bioinformatics.2007,8:431.
[121]Zhang F. and Drabier R.IPAD: the Integrated Pathway Analysis Database forSystematic Enrichment Analysis[J].BMC Bioinformatics.2012,13Suppl15(S7).
[122]Bansal M.,Belcastro V.,Ambesi-Impiombato A., et al.How to infer gene networksfrom expression profiles[J].Mol Syst Biol.2007,3(78).
[123]Hwang S.,Son S. W.,Kim S. C., et al.A protein interaction network associated withasthma[J].J Theor Biol.2008,252(4):722-31.
[124]Ozgur A.,Vu T.,Erkan G., et al.Identifying gene-disease associations using centralityon a literature mined gene-interaction network[J].Bioinformatics.2008,24(13):i277-85.
[125]Raman K.Construction and analysis of protein-protein interaction networks[J].Autom Exp.2010,2(1):2.
[126]Buys T. P.,Chari R.,Lee E. H., et al.Genetic changes in the evolution of multidrugresistance for cultured human ovarian cancer cells[J].Genes Chromosomes Cancer.2007,46(12):1069-79.
[127]Zeller C.,Dai W.,Steele N. L., et al.Candidate DNA methylation drivers of acquiredcisplatin resistance in ovarian cancer identified by methylome and expression profiling[J].Oncogene.2012,31(42):4567-76.
[128]Lavarino C.,Pilotti S.,Oggionni M., et al.p53gene status and response toplatinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma[J].J Clin Oncol.2000,18(23):3936-45.
[129]Moliterni A.,Menard S.,Valagussa P., et al.HER2overexpression and doxorubicin inadjuvant chemotherapy for resectable breast cancer[J].J Clin Oncol.2003,21(3):458-62.
[130]孔北华,W.-x ZHENG.重视卵巢癌的二元论模型与卵巢外起源新说[J].中华妇产科杂志.2011,46(10):721-3.
[131]Plumb J. A.,Strathdee G.,Sludden J., et al.Reversal of drug resistance in humantumor xenografts by2'-deoxy-5-azacytidine-induced demethylation of the hMLH1genepromoter[J]. Cancer Res.2000,60(21):6039-44.
[132]Wiedemeyer W. R.,Beach J. A. and Karlan B. Y.Reversing Platinum Resistance inHigh-Grade Serous Ovarian Carcinoma: Targeting BRCA and the Homologous Recom-bination System[J].Front Oncol.2014,4:34.
[133]Gu J.,Tang Y.,Liu Y., et al.Murine double minute2siRNA and wild-type p53genetherapy enhances sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatinchemotherapy in vitro and in vivo[J].Cancer Lett.2014,343(2):200-9.
[134]Zeimet A. G. and Marth C.Why did p53gene therapy fail in ovarian cancer[J].Lancet Oncol.2003,4(7):415-22.
[135]Calin G. A.,Sevignani C.,Dumitru C. D., et al.Human microRNA genes arefrequently located at fragile sites and genomic regions involved in cancers[J].Proc Natl AcadSci U S A.2004,101(9):2999-3004.
[136]Lujambio A. and Lowe S. W.The microcosmos of cancer[J].Nature.2012,482(7385):347-55.
[137]Png K. J.,Halberg N.,Yoshida M., et al.A microRNA regulon that mediatesendothelial recruitment and metastasis by cancer cells[J].Nature.2012,481(7380):190-4.
[138]Su X.,Chakravarti D.,Cho M. S., et al.TAp63suppresses metastasis throughcoordinate regulation of Dicer and miRNAs[J].Nature.2010,467(7318):986-90.
[139]Suzuki H. I.,Yamagata K.,Sugimoto K., et al.Modulation of microRNA processingby p53[J].Nature.2009,460(7254):529-33.
[140]Blower P. E.,Verducci J. S.,Lin S., et al.MicroRNA expression profiles for theNCI-60cancer cell panel[J].Mol Cancer Ther.2007,6(5):1483-91.
[141]Blower P. E.,Chung J. H.,Verducci J. S., et al.MicroRNAs modulate thechemosensitivity of tumor cells[J].Mol Cancer Ther.2008,7(1):1-9.
[142]Iida K.,Fukushi J.,Matsumoto Y., et al.miR-125b develops chemoresistance inEwing sarcoma/primitive neuroectodermal tumor[J].Cancer Cell Int.2013,13(1):21.
[143]Bai Y.,Liao H.,Liu T., et al.MiR-296-3p regulates cell growth and multi-drugresistance of human glioblastoma by targeting ether-a-go-go (EAG1)[J].Eur J Cancer.2013,49(3):710-24.
[144]Yang S. M.,Huang C.,Li X. F., et al.miR-21confers cisplatin resistance in gastriccancer cells by regulating PTEN[J].Toxicology.2013,306:162-8.
[145]Hong L.,Yang Z.,Ma J., et al.Function of miRNA in controlling drug resistance ofhuman cancers[J].Curr Drug Targets.2013,14(10):1118-27.
[146]Drayton R. M.,Dudziec E.,Peter S., et al.Reduced Expression of miRNA-27aModulates Cisplatin Resistance in Bladder Cancer by Targeting the Cystine/GlutamateExchanger SLC7A11[J].Clin Cancer Res.2014,20(7):1990-2000.
[147]Murray-Stewart T.,Hanigan C. L.,Woster P. M., et al.Histone deacetylase inhibitionovercomes drug resistance through a miRNA-dependent mechanism[J].Mol Cancer Ther.2013,12(10):2088-99.
[148]Schmittgen T. D.,Lee E. J.,Jiang J., et al.Real-time PCR quantification of precursorand mature microRNA[J].Methods.2008,44(1):31-8.
[149]Castoldi M.,Schmidt S.,Benes V., et al.A sensitive array for microRNA expressionprofiling (miChip) based on locked nucleic acids (LNA)[J].RNA.2006,12(5):913-20.
[150]Maskos U. and Southern E. M.Oligonucleotide hybridizations on glass supports: anovel linker for oligonucleotide synthesis and hybridization properties of oligonucleotidessynthesised in situ[J].Nucleic Acids Res.1992,20(7):1679-84.
[151]Ambros V.The functions of animal microRNAs[J].Nature.2004,431(7006):350-5.
[152]Bartel D. P.MicroRNAs: genomics, biogenesis, mechanism, and function[J].Cell.2004,116(2):281-97.
[153]Du T. and Zamore P. D.microPrimer: the biogenesis and function of microRNA[J].Development.2005,132(21):4645-52.
[154]Zhang B.,Pan X.,Cobb G. P., et al.microRNAs as oncogenes and tumor suppressors[J].Dev Biol.2007,302(1):1-12.
[155]Xu X.Same computational analysis, different miRNA target predictions[J].NatMethods.2007,4(3):191.
[156]Lewis B. P.,Shih I. H.,Jones-Rhoades M. W., et al.Prediction of mammalian micro-RNA targets[J].Cell.2003,115(7):787-98.
[157]Krek A.,Grun D.,Poy M. N., et al.Combinatorial microRNA target predictions[J].Nat Genet.2005,37(5):495-500.
[158]Yang H.,Kong W.,He L., et al.MicroRNA expression profiling in human ovariancancer: miR-214induces cell survival and cisplatin resistance by targeting PTEN[J].CancerRes.2008,68(2):425-33.
[159]Sorrentino A.,Liu C. G.,Addario A., et al.Role of microRNAs in drug-resistantovarian cancer cells[J]. Gynecol Oncol.2008,111(3):478-86.
[160]Kumar S.,Kumar A.,Shah P. P., et al.MicroRNA signature of cis-platin resistant vs.cis-platin sensitive ovarian cancer cell lines[J].J Ovarian Res.2011,4(1):17.
[161]van Jaarsveld M. T.,Helleman J.,Boersma A. W., et al.miR-141regulates KEAP1and modulates cisplatin sensitivity in ovarian cancer cells[J].Oncogene.2013,32(36):4284-93.
[162]Xiang Y.,Ma N.,Wang D., et al.MiR-152and miR-185co-contribute to ovariancancer cells cisplatin sensitivity by targeting DNMT1directly: a novel epigenetic therapyindependent of decitabine[J].Onco-gene.2014,33(3):378-86.
[163]Huh J. H.,Kim T. H.,Kim K., et al.Dysregulation of miR-106a and miR-591conferspaclitaxel resistance to ovarian cancer[J].Br J Cancer.2013,109(2):452-61.
[164]Cittelly D. M.,Dimitrova I.,Howe E. N., et al.Restoration of miR-200c to ovariancancer reduces tumor burden and increases sensitivity to paclitaxel[J].Mol CancerTher.2012,11(12):2556-65.
[165]Yang C.,Cai J.,Wang Q., et al.Epigenetic silencing of miR-130b in ovarian cancerpromotes the development of multidrug resistance by targeting colony-stimulating factor1[J].Gynecol Oncol.2012,124(2):325-34.
[166]Mitamura T.,Watari H.,Wang L., et al.Downregulation of miRNA-31inducestaxane resistance in ovarian cancer cells through increase of receptor tyrosine kinaseMET[J].Onco-genesis.2013,2:e40.
[167]Ruigrok Y. M.,Wijmenga C.,Rinkel G. J., et al.Genomewide linkage in a largeDutch family with intracranial aneurysms: replication of2loci for intracranial aneurysms tochromosome1p36.11-p36.13and Xp22.2-p22.32[J].Stroke.2008,39(4):1096-102.
[168]Feigin V. L. and Findlay M.Advances in subarachnoid hemorrhage[J].Stroke.2006,37(2):305-8.
[169]Juvela S.Natural history of unruptured intracranial aneurysms: risks for aneurysmformation, growth, and rupture[J].Acta Neurochir Suppl.2002,82:27-30.
[170]van der Voet M.,Olson J. M.,Kuivaniemi H., et al.Intracranial aneurysms in Finnishfamilies: confirmation of linkage and refinement of the interval to chromosome19q13.3[J].Am J Hum Genet.2004,74(3):564-71.
[171]Shmulevich I.,Dougherty E. R.,Kim S., et al.Probabilistic Boolean Networks: arule-based uncertainty model for gene regulatory networks[J].Bioinformatics.2002,18(2):261-74.
[172]Chen T.,He H. L. and Church G. M.Modeling gene expression with differentialequations[J].Pac Symp Biocomput.1999:29-40.
[173]Herrero J.,Valencia A. and Dopazo J.A hierarchical unsupervised growing neuralnetwork for clustering gene expression patterns[J].Bioinformatics.2001,17(2):126-36.
[174]Imoto S.,Kim S.,Goto T., et al.Bayesian network and nonparametric heteroscedasticregression for nonlinear modeling of genetic network[J].J Bioinform Comput Biol.2003,1(2):231-52.
[175]Nam S.,Li M.,Choi K., et al.MicroRNA and mRNA integrated analysis (MMIA): aweb tool for examining biological functions of microRNA expression[J].Nucleic AcidsRes.2009,37(Web Server issue):W356-62.
[176]Sales G.,Coppe A.,Bisognin A., et al.MAGIA, a web-based tool for miRNA andGenes Integrated Analysis[J].Nucleic Acids Res.2010,38(Web Server issue):W352-9.
[177]Bisognin A.,Sales G.,Coppe A., et al.MAGIA(2):from miRNA and genes expressiondata integrative analysis to microRNA-transcription factor mixed regulatory circuits (2012update)[J].Nucleic Acids Res.2012,40(Web Server issue):W13-21.
[178]Devaraj S. and Natarajan J.miRNA-mRNA network detects hub mRNAs andcancer specific miRNAs in lung cancer[J].In Silico Biol.2011,11(5-6):281-95.
[179]Zhang W.,Edwards A.,Fan W., et al.miRNA-mRNA correlation-network modules inhuman prostate cancer and the differences between primary and metastatic tumorsubtypes[J].PLoS One.2012,7(6):e40130.
[180]Delfino K. R. and Rodriguez-Zas S. L.Transcription factor-microRNA-target genenetworks associated with ovarian cancer survival and recurrence[J].PLoS One.2013,8(3):e58608.
[1]Jemal A.,Siegel R.,Xu J., et al.Cancer statistics,2010[J].CA Cancer J Clin.2010,60(5):277-300.
[2]Samrao D.,Wang D.,Ough F., et al.Histologic parameters predictive of diseaseoutcome in women with advanced stage ovarian carcinoma treated with neoadjuvantchemotherapy[J].Transl Oncol.2012,5(6):469-74.
[3]Matsuo K.,Eno M. L.,Im D. D., et al.Clinical relevance of extent of extreme drugresistance in epithelial ovarian carcinoma[J].Gynecol Oncol.2010,116(1):61-5.
[4]Bartel D. P.MicroRNAs: genomics, biogenesis, mechanism, and function[J].Cell.2004,116(2):281-97.
[5]Xiang X.,Zhuang X.,Ju S., et al.miR-155promotes macroscopic tumor formation yetinhibits tumor dissemination from mammary fat pads to the lung by preventing EMT[J].Oncogene.2011,30(31):3440-53.
[6]Gao W.,Lu X.,Liu L., et al.MiRNA-21: a biomarker predictive for platinum-basedadjuvant chemotherapy response in patients with non-small cell lung cancer[J].Cancer BiolTher.2012,13(5):330-40.
[7]Aguirre-Gamboa R. and Trevino V.SurvMicro:assessment of miRNA-based prognos-tic signatures for cancer clinical outcomes by multivariate survival analysis[J]. Bioinformatics.2014,30(11):1630-2.
[8]Ahmed F. E.miRNA as markers for the diagnostic screening of colon cancer[J].ExpertRev Anticancer Ther.2014,14(4):463-85.
[9]Carstens J. L.,Lovisa S. and Kalluri R.Microenvironment-dependent cues triggermiRNA-regulated feedback loop to facilitate the EMT/MET switch[J].J Clin Invest.2014,124(4):1458-60.
[10]Drayton R. M.,Dudziec E.,Peter S., et al.Reduced Expression of miRNA-27aModulates Cisplatin Resistance in Bladder Cancer by Targeting the Cystine/GlutamateExchanger SLC7A11[J].Clin Cancer Res.2014,20(7):1990-2000.
[11]Chen Y.,Sun Y.,Chen L., et al.miRNA-200c increases the sensitivity of breast cancercells to doxorubicin through the suppression of E-cadherin-mediated PTEN/Akt signaling[J].Mol Med Rep.2013,7(5):1579-84.
[12]Zhang L.,Pickard K.,Jenei V., et al.miR-153supports colorectal cancer progressionvia pleiotropic effects that enhance invasion and chemotherapeutic resistance[J].Cancer Res.2013,73(21):6435-47.
[13]Sorrentino A.,Liu C. G.,Addario A., et al.Role of microRNAs in drug-resistantovarian cancer cells[J].Gyne-col Oncol.2008,111(3):478-86.
[14]Krek A.,Grun D.,Poy M. N., et al.Combinatorial microRNA target predictions[J].NatGenet.2005,37(5):495-500.
[15]Yang S. M.,Huang C.,Li X. F., et al.miR-21confers cisplatin resistance in gastriccancer cells by regulating PTEN[J].Toxicology.2013,306:162-8.
[16]Medina P. P.,Nolde M. and Slack F. J.OncomiR addiction in an in vivo model ofmicroRNA-21-induced pre-B-cell lymphoma[J].Nature.2010,467(7311):86-90.
[17]Hatley M. E.,Patrick D. M.,Garcia M. R., et al.Modulation of K-Ras-dependent lungtumorigenesis by MicroRNA-21[J].Cancer Cell.2010,18(3):282-93.
[18]Farazi T. A.,Horlings H. M.,Ten Hoeve J. J., et al.MicroRNA sequence andexpression analysis in breast tumors by deep sequencing[J].Cancer Res.2011,71(13):4443-53.
[19]Yao T.,Rao Q.,Liu L., et al.Exploration of tumor-suppressive microRNAs silencedby DNA hypermethy-lation in cervical cancer[J].Virol J.2013,10:175.
[20]Mace T. A.,Collins A. L.,Wojcik S. E., et al.Hypoxia induces the overexpression ofmicroRNA-21in pancreatic cancer cells[J].J Surg Res.2013,184(2):855-60.
[21]Li X.,Lu Y.,Chen Y., et al.MicroRNA profile of paclitaxel-resistant serous ovariancarcinoma based on formalin-fixed paraffin-embedded samples[J].BMC Cancer.2013,13:216.
[22]Wyman S. K.,Parkin R. K.,Mitchell P. S., et al.Repertoire of microRNAs in epithelialovarian cancer as determined by next generation sequencing of small RNA cDNAlibraries[J].PLoS One.2009,4(4):e5311.
[23]Laios A.,O'Toole S.,Flavin R., et al.Potential role of miR-9and miR-223in recurrentovarian cancer[J].Mol Cancer.2008,7:35.
[24]Dahiya N. and Morin P. J.MicroRNAs in ovarian carcinomas[J].Endocr RelatCancer.2010,17(1):F77-89.
[25]Hu X.,Macdonald D. M.,Huettner P. C., et al.A miR-200microRNA cluster asprognostic marker in advanced ovarian cancer[J].Gynecol Oncol.2009,114(3):457-64.
[26]Smith C. M.,Watson D. I.,Leong M. P., et al.miR-200family expression is down-regulated upon neoplastic progression of Barrett's esophagus[J].World J Gastroenterol.2011,17(8):1036-44.
[27]Cochrane D. R.,Howe E. N.,Spoelstra N. S., et al.Loss of miR-200c: A Marker ofAggressiveness and Chemoresistance in Female Reproductive Cancers[J].J Oncol.2010,2010:821717.
[28]Kozaki K.,Imoto I.,Mogi S., et al.Exploration of tumor-suppressive microRNAssilenced by DNA hypermethylation in oral cancer[J].Cancer Res.2008,68(7):2094-105.
[29]Porkka K. P.,Pfeiffer M. J.,Waltering K. K., et al.MicroRNA expression profiling inprostate cancer[J].Cancer Res.2007,67(13):6130-5.
[30]Xiang Y.,Ma N.,Wang D., et al.MiR-152and miR-185co-contribute to ovariancancer cells cisplatin sensitivity by targeting DNMT1directly: a novel epigenetic therapyindependent of decitabine[J].Onco-gene.2014,33(3):378-86.
[1]L'Esperance S.,Popa I.,Bachvarova M., et al.Gene expression profiling of pairedovarian tumors obtained prior to and following adjuvant chemotherapy: molecular signaturesof chemoresistant tumors[J].Int J Oncol.2006,29(1):5-24.
[2]Schena M.,Shalon D.,Davis R. W., et al.Quantitative monitoring of gene expressionpatterns with a complementary DNA microarray[J].Science.1995,270(5235):467-70.
[3]Lisowska K. M.,Olbryt M.,Dudaladava V., et al.Gene expression analysis in ovariancancer faults and hints from DNA microarray study[J].Front Oncol.2014,4:6.
[4]Ng C. F.,Xu J. Y.,Li M. S., et al.Identification of FHL2-regulated genes in liver bymicroarray and bioinformatics analysis[J].J Cell Biochem.2014,115(4):744-53.
[5]Xu Y. C.,Liu Q.,Dai J. Q., et al.Tissue microarray analysis of X-linked inhibitor ofapoptosis (XIAP) expression in breast cancer patients[J].Med Oncol.2014,31(3):764.
[6]Shimizu K. K. and Purugganan M. D.Evolutionary and ecological genomics ofArabidopsis[J].Plant Physiol.2005,138(2):578-84.
[7]高远田.,秦松.植物进化中的正选择作用[J].植物学通报.2008,25(4):401-406.
[8]McCormick M. L.,Gavrila D. and Weintraub N. L.Role of oxidative stress in thepathogenesis of abdominal aortic aneurysms[J].Arterioscler Thromb Vasc Biol.2007,27(3):461-9.
[9]Marchese E.,Vignati A.,Albanese A., et al.Comparative evaluation of genome-widegene expression profiles in ruptured and unruptured human intracranial aneurysms[J].J BiolRegul Homeost Agents.2010,24(2):185-95.
[10]Aznavoorian S.,Murphy A. N.,Stetler-Stevenson W. G., et al.Molecular aspects oftumor cell invasion and metastasis[J].Cancer.1993,71(4):1368-83.
[11]Akiyama S.,Satake N. and Ishioka C.C-kit and other receptor tyrosine kinases play acrucial role in oncogenic signaling and drug-resistance[J].Nihon Rinsho.2012,70Suppl8:36-40.
[12]Chau W. K.,Ip C. K.,Mak A. S., et al.c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/beta-catenin-ATP-bindingcassette G2signaling[J].Onco-gene.2013,32(22):2767-81.
[13]Luo L.,Zeng J.,Liang B., et al.Ovarian cancer cells with the CD117phenotype arehighly tumorigenic and are related to chemotherapy outcome[J].Exp Mol Pathol.2011,91(2):596-602.
[14]Montemurro M. and Bauer S.Treatment of gastrointestinal stromal tumor afterimatinib and sunitinib[J].Curr Opin Oncol.2011,23(4):367-72.
[15]Tanahashi T.,Osada S.,Yamada A., et al.Extracellular signal-regulated kinase and Aktactivation play a critical role in the process of hepatocyte growth factor-inducedepithelial-mesenchymal transition[J].Int J Oncol.2013,42(2):556-64.
[16]Razzak M.Targeted therapies: hepatocyte growth factor-a culprit of drugresistance[J]. Nat Rev Clin Oncol.2012,9(8):429.
[17]Olivero M.,Ruggiero T.,Saviozzi S., et al.Genes regulated by hepatocyte growthfactor as targets to sensitize ovarian cancer cells to cisplatin[J].Mol Cancer Ther.2006,5(5):1126-35.
[18]Saharinen P. and Alitalo K.Double target for tumor mass destruction[J].J Clin Invest.2003,111(9):1277-80.
[19]Bergers G.,Song S.,Meyer-Morse N., et al.Benefits of targeting both pericytes andendothelial cells in the tumor vasculature with kinase inhibitors[J].J Clin Invest.2003,111(9):1287-95.
[20]Shchemelinin I.,Sefc L. and Necas E.Protein kinase inhibitors[J].Folia Biol (Praha).2006,52(4):137-48.
[21]Tian K.,Rajendran R.,Doddananjaiah M., et al.Dynamics of DNA damage inducedpathways to cancer[J].PLoS One.2013,8(9):e72303.
[22]Finn R. S.,Dering J.,Ginther C., et al.Dasatinib, an orally active small moleculeinhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/"triple-negative"breast cancer cell lines growing in vitro[J].Breast Cancer Res Treat.2007,105(3):319-26.
[23]Pichot C. S.,Hartig S. M.,Xia L., et al.Dasatinib synergizes with doxorubicin toblock growth, migration, and invasion of breast cancer cells[J].Br J Cancer.2009,101(1):38-47.
[24]Gomez-Casal R.,Bhattacharya C.,Ganesh N., et al.Non-small cell lung cancer cellssurvived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymaltransition phenotypes[J]. Mol Cancer.2013,12(1):94.
[25]Keshava N.,Gubba S. and Tekmal R. R.Overexpression of macrophage colony-stimulating factor (CSF-1) and its receptor, c-fms, in normal ovarian granulosa cells leads tocell proliferation and tumorigenesis[J].J Soc Gynecol Investig.1999,6(1):41-9.
[26]Toy E. P.,Azodi M.,Folk N. L., et al.Enhanced ovarian cancer tumorigenesis andmetastasis by the macrophage colony-stimulating factor[J].Neoplasia.2009,11(2):136-44.
[27]Chambers S. K.Role of CSF-1in progression of epithelial ovarian cancer[J].FutureOncol.2009,5(9):1429-40.
[28]Abi Saab W. F.,Brown M. S. and Chadee D. N.MLK4beta functions as a negativeregulator of MAPK signaling and cell invasion[J].Oncogenesis.2012,1:e6.
[29]Narayan G.,Freddy A. J.,Xie D., et al.Promoter methylation-mediated inactivation ofPCDH10in acute lymphoblastic leukemia contributes to chemotherapy resistance[J].GenesChromosomes Cancer.2011,50(12):1043-53.
[30]Ding K.,Su Y.,Pang L., et al.Inhibition of apoptosis by downregulation of hBex1, anovel mechanism, contributes to the chemoresistance of Bcr/Abl+leukemic cells[J].Carcinogenesis.2009,30(1):35-42.
[31]Rikiyama T.,Curtis J.,Oikawa M., et al.GCF2: expression and molecular analysis ofrepression[J]. Biochim Biophys Acta.2003,1629(1-3):15-25.
[32]Li J. P.,Cao N. X.,Jiang R. T., et al.Knockdown of GCF2/LRRFIP1by RNAi CausesCell Growth Inhibition and Increased Apoptosis in Human Hepatoma HepG2Cells[J].AsianPac J Cancer Prev.2014,15(6):2753-8.
[33]Yang W.,He M.,Zhao J., et al.Association of ITGA3gene polymorphisms withsusceptibility and clinicopathological characteristics of osteosarcoma[J].Med Oncol.2014,31(2):826.
[34]Ibrahim S. A.,Yip G. W.,Stock C., et al.Targeting of syndecan-1by microRNAmiR-10b promotes breast cancer cell motility and invasiveness via a Rho-GTPase-andE-cadherin-dependent mechanism[J].Int J Cancer.2012,131(6):E884-96.
[1]Ruigrok Y. M.,Wijmenga C.,Rinkel G. J., et al.Genomewide linkage in a large Dutchfamily with intracranial aneurysms: replication of2loci for intracranial aneurysms tochromosome1p36.11-p36.13and Xp22.2-p22.32[J].Stroke.2008,39(4):1096-102.
[2]Nam S.,Li M.,Choi K., et al.MicroRNA and mRNA integrated analysis (MMIA): aweb tool for examining biological functions of microRNA expression[J].Nucleic AcidsRes.2009,37(Web Server issue):W356-62.
[3]Sales G.,Coppe A.,Bisognin A., et al.MAGIA, a web-based tool for miRNA and GenesIntegrated Analysis[J].Nucleic Acids Res.2010,38(Web Server issue):W352-9.
[4]Bisognin A.,Sales G.,Coppe A., et al.MAGIA(2): from miRNA and genes expressiondata integrative analysis to microRNA-transcription factor mixed regulatory circuits (2012update)[J].Nucleic Acids Res.2012,40(Web Server issue):W13-21.
[5]Saito R.,Smoot M. E.,Ono K., et al.A travel guide to Cytoscape plugins[J].NatMethods.2012,9(11):1069-76.
[6]Feigin V. L. and Findlay M.Advances in subarachnoid hemorrhage[J].Stroke.2006,37(2):305-8.
[7]Juvela S.Natural history of unruptured intracranial aneurysms: risks for aneurysmformation, growth, and rupture[J].Acta Neurochir Suppl.2002,82(27-30.
[8]van der Voet M.,Olson J. M.,Kuivaniemi H., et al.Intracranial aneurysms in Finnishfamilies: confirmation of linkage and refinement of the interval to chromosome19q13.3[J].Am J Hum Genet.2004,74(3):564-71.
[9]Hu X.,Macdonald D. M.,Huettner P. C., et al.A miR-200microRNA cluster asprognostic marker in advanced ovarian cancer[J].Gynecol Oncol.2009,114(3):457-64.
[10]Smith C. M.,Watson D. I.,Leong M. P., et al.miR-200family expression isdown-regulated upon neoplastic progression of Barrett's esophagus[J].World JGastroenterol.2011,17(8):1036-44.
[11]Sun Y.,Shen S.,Liu X., et al.miR-429inhibits cells growth and invasion and regulatesEMT-related marker genes by targeting Onecut2in colorectal carcinoma[J].Mol Cell Biochem.2014,390(12):19-30.
[12]Cochrane D. R.,Howe E. N.,Spoelstra N. S., et al.Loss of miR-200c: A Marker ofAggressiveness and Chemoresistance in Female Reproductive Cancers[J].J Oncol.2010:1-12.
[13]Hapkova I.,Skarda J.,Rouleau C., et al.High expression of the RNA-binding proteinRBPMS2in gastrointestinal stromal tumors[J].Exp Mol Pathol.2013,94(2):314-21.
[14]Skawran B.,Steinemann D.,Becker T., et al.Loss of13q is associated with genesinvolved in cell cycle and proliferation in dedifferentiated hepatocellular carcinoma[J].ModPathol.2008,21(12):1479-89.
[15]Gentles A. J.,Plevritis S. K.,Majeti R., et al.Association of a leukemic stem cell geneexpression signature with clinical outcomes in acute myeloid leukemia[J].JAMA.2010,304(24):2706-15.
[16]Xu X.,Patrakka J.,Sistani L., et al.Expression of novel podocyte-associated proteinssult1b1and ankrd25[J].Nephron Exp Nephrol.2011,117(2):e39-46.
[17]Kozaki K.,Imoto I.,Mogi S., et al.Exploration of tumor-suppressive microRNAssilenced by DNA hypermethylation in oral cancer[J].Cancer Res.2008,68(7):2094-105.
[18]Arai K.,Sakamoto R.,Kubota D., et al.Proteomic approach toward molecularbackgrounds of drug resistance of osteosarcoma cells in spheroid culturesystem[J].Proteomics.2013,13(15):2351-60.
[19]Cho H. J.,Baek K. E.,Kim I. K., et al.Proteomics-based strategy to delineate themolecular mechanisms of RhoGDI2-induced metastasis and drug resistance in gastriccancer[J]. J Proteome Res.2012,11(4):2355-64.
[20]Tang S.,Huang W.,Zhong M., et al.Identification Keratin1as a cDDP-resistantprotein in nasopharyngeal carcinoma cell lines[J].J Proteomics.2012,75(8):2352-60.
[21]Osmak M.,Niksic D.,Brozovic A., et al.Drug resistant tumor cells have increasedlevels of tumor markers for invasion and metastasis[J].Anticancer Res.1999,19(4B):3193-7.
[22]Sagulenko V.,Muth D.,Sagulenko E., et al.Cathepsin D protects humanneuroblastoma cells from doxorubicin-induced cell death[J].Carcinogenesis.2008,29(10):1869-77.
[23]Unsicker K.,Spittau B. and Krieglstein K.The multiple facets of the TGF-beta familycytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1[J].CytokineGrowth Factor Rev.2013,24(4):373-84.
[24]Mimeault M.,Johansson S. L. and Batra S. K.Marked improvement of cytotoxiceffects induced by docetaxel on highly metastatic and androgen-independent prostate cancercells by downregulating macrophage inhibitory cytokine-1[J].Br J Cancer.2013,108(5):1079-91.
[25]Barderas R.,Mendes M.,Torres S., et al.In-depth characterization of the secretome ofcolorectal cancer metastatic cells identifies key proteins in cell adhesion, migration, andinvasion[J].Mol Cell Proteomics.2013,12(6):1602-20.
[26]Rotkrua P.,Akiyama Y.,Hashimoto Y., et al.MiR-9downregulates CDX2expressionin gastric cancer cells[J].Int J Cancer.2011,129(11):2611-20.
[27]Uhlmann S.,Zhang J. D.,Schwager A., et al.miR-200bc/429cluster targetsPLCgamma1and differentially regulates proliferation and EGF-driven invasion thanmiR-200a/141in breast cancer[J].Oncogene.2010,29(30):4297-306.
[28]Adam L.,Zhong M.,Choi W., et al.miR-200expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growthfactor receptor therapy[J].Clin Cancer Res.2009,15(16):5060-72.
[29]Tang H.,Liu X.,Wang Z., et al.Interaction of hsa-miR-381and glioma suppressorLRRC4is involved in glioma growth[J].Brain Res.2011,1390:21-32.
[30]Papp G.,Krausz T.,Stricker T. P., et al.SMARCB1expression in epithelioid sarcomais regulated by miR-206, miR-381, and miR-671-5p on Both mRNA and proteinlevels[J].Genes Chromosomes Cancer.2014,53(2):168-76.
[31]Wu X. M.,Shao X. Q.,Meng X. X., et al.Genome-wide analysis of microRNA andmRNA expression signatures in hydroxycamptothecin-resistant gastric cancer cells[J].ActaPharmacol Sin.2011,32(2):259-69.
[32]Izquierdo J. M.,Alcalde J.,Carrascoso I., et al.Knockdown of T-cell intracellularanti-gens triggers cell proliferation, invasion and tumour growth[J].Biochem J.2011,435(2):337-44.
[33]Zhang L.,Volinia S.,Bonome T., et al.Genomic and epigenetic alterations deregulatemicroRNA expression in human epithelial ovarian cancer[J].Proc Natl Acad Sci U S A.2008,105(19):7004-9.
[34]Hwang-Verslues W. W.,Chang P. H.,Wei P. C., et al.miR-495is upregulated by E12/E47in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance viadownregulation of E-cadherin and REDD1[J].Oncogene.2011,30(21):2463-74.
[35]Trueb B.,Zhuang L.,Taeschler S., et al.Characterization of FGFRL1, a novelfibroblast growth factor (FGF) receptor preferentially expressed in skeletal tissues[J].J BiolChem.2003,278(36):33857-65.
[36]Schild C. and Trueb B.Aberrant expression of FGFRL1, a novel FGF receptor, inovarian tumors[J].Int J Mol Med.2005,16(6):1169-73.
[37]Xu Y.,Ohms S. J.,Li Z., et al.Changes in the expression of miR-381and miR-495areinversely associated with the expression of the MDR1gene and development of multi-drugresistance[J].PLoS One.2013,8(11):e82062.
[38]Shih K. K.,Qin L. X.,Tanner E. J., et al.A microRNA survival signature (MiSS) foradvanced ovarian cancer[J].Gynecol Oncol.2011,121(3):444-50.
[39]Liguori L.,Andolfo I.,de Antonellis P., et al.The metallophosphodiesterase Mpped2impairs tumorigenesis in neuroblastoma[J].Cell Cycle.2012,11(3):569-81.
[40]Song B.,Wang Y.,Xi Y., et al.Mechanism of chemoresistance mediated by miR-140in human osteosarcoma and colon cancer cells[J].Oncogene.2009,28(46):4065-74.
[41]Hummel R.,Wang T.,Watson D. I., et al.Chemotherapy-induced modification ofmicroRNA expression in esophageal cancer[J].Oncol Rep.2011,26(4):1011-7.
[2]Jemal A.,Siegel R.,Xu J., et al.Cancer statistics,2010[J].CA Cancer J Clin.2010,60(5):277-300.
[3]Siegel R.,Naishadham D. and Jemal A.Cancer statistics,2012[J].CA Cancer J Clin.2012,62(1):10-29.
[4]Samrao D.,Wang D.,Ough F.,et al.Histologic parameters predictive of diseaseoutcome in women with advanced stage ovarian carcinoma treated with neoadjuvantchemotherapy[J]. Transl Oncol.2012,5(6):469-74.
[5]Matsuo K.,Eno M. L.,Im D. D., et al.Clinical relevance of extent of extreme drugresistance in epithelial ovarian carcinoma[J].Gynecol Oncol.2010,116(1):61-5.
[6] National Comprehensive Cancer Network: The NCCN clinical practice guidelines inoncology ovarian cancer(version1).[J]2014.
[7]du Bois A.,Luck H. J.,Meier W., et al.A randomized clinical trial ofcisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer[J].JNatl Cancer Inst.2003,95(17):1320-9.
[8]Katsumata N.,Yasuda M.,Takahashi F., et al.Dose-dense paclitaxel once a week incombination with carboplatin every3weeks for advanced ovarian cancer: a phase3,open-label, randomised controlled trial[J].Lancet.2009,374(9698):1331-8.
[9]Pignata S.,Scambia G.,Katsaros D., et al.Carboplatin plus paclitaxel once a weekversus every3weeks in patients with advanced ovarian cancer (MITO-7): a randomised,multicentre, open-label, phase3trial[J].Lancet Oncol.2014,15(4):396-405.
[10]Kumagai M.,Fujii T.,Komatsu M., et al.Paclitaxel plus carboplatin in ovariancancer-comparison of adverse effects between monthly and weekly administration[J].Gan ToKagaku Ryoho.2004,31(4):555-9.
[11]Katsumata N.,Yasuda M.,Isonishi S., et al.Long-term results of dose-dense paclitaxeland carboplatin versus conventional paclitaxel and carboplatin for treatment of advancedepithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG3016): a randomised,controlled, open-label trial[J].Lancet Oncol.2013,14(10):1020-6.
[12]Piccart M. J.,Du Bois A.,Gore M. E., et al.A new standard of care for treatment ofovarian cancer[J].Eur J Cancer.2000,36(1):10-2.
[13]Winter-Roach B. A.,Kitchener H. C. and Lawrie T. A.Adjuvant (post-surgery)chemotherapy for early stage epithelial ovarian cancer[J].Cochrane Database SystRev.2012,3(CD004706).
[14]Lawrie T. A.,Rabbie R.,Thoma C., et al.Pegylated liposomal doxorubicin forfirst-line treatment of epithelial ovarian cancer[J].Cochrane Database Syst Rev.2013,10(CD010482).
[15]Staropoli N.,Ciliberto D.,Botta C., et al.Pegylated liposomal doxorubicin in themanagement of ovarian cancer: A systematic review and metaanalysis of randomizedtrials[J].Cancer Biol Ther.2014,15(6):707-20.
[16]Heintz AP O. F., Maisonneuve P,et al.FIGO (International Federation of Gynecologyand Obstetrics)26th Annual Report on the Results of Treatment in GynecologicalCancer[J].Int J Gynaecol Obstet.2006,95Suppl1(S1-257).
[17]Gadducci A.,Cosio S.,Zola P., et al.Prognostic factors and clinical outcome ofpatients with recurrent early-stage epithelial ovarian cancer: an Italian multicenterretrospective study[J].Int J Gynecol Cancer.2013,23(3):461-8.
[18]Winter W. E.,3rd,Maxwell G. L.,Tian C., et al.Prognostic factors for stage IIIepithelial ovarian cancer: a Gynecologic Oncology Group Study[J].J Clin Oncol.2007,25(24):3621-7.
[19]Fu Y.,Wang X.,Pan Z., et al.Clinical outcomes and prognostic factors of patients withepithelial ovarian cancer subjected to first-line treatment: a retrospective study of251cases[J].Front Med.2014,8(1):91-5.
[20]Mackay H. J.,Brady M. F.,Oza A. M., et al.Prognostic relevance of uncommonovarian histology in women with stage III/IV epithelial ovarian cancer[J].Int J GynecolCancer.2010,20(6):945-52.
[21]Gershenson D. M.,Sun C. C.,Lu K. H., et al.Clinical behavior of stage II-IVlow-grade serous carcinoma of the ovary[J].Obstet Gynecol.2006,108(2):361-8.
[22]Bosari S.,Viale G.,Radaelli U., et al.p53accumulation in ovarian carcinomas and itsprognostic implications[J].Hum Pathol.1993,24(11):1175-9.
[23]Kowalski L.D.,Kanbour A.I.,Price F.V.,et al.A case-matched molecular comparisonof extraovarian versus primary ovarian adenocarcinoma[J].Cancer.1997,79(8):1587-94.
[24]Skirnisdottir I. and Sorbe B.Prognostic factors for surgical outcome and survival in447women treated for advanced (FIGO-stages III-IV) epithelial ovarian carcinoma[J].Int JOncol.2007,30(3):727-34.
[25]林仲秋,李晶.妇科肿瘤学原理与实践(第5版),北京:[J].人民卫生出版社.2012,900.
[26]Marusyk A.,Almendro V. and Polyak K.Intra-tumour heterogeneity: a looking glassfor cancer[J].Nat Rev Cancer.2012,12(5):323-34.
[27]Khalique L.,Ayhan A.,Weale M. E., et al.Genetic intra-tumour heterogeneity inepithelial ovarian cancer and its implications for molecular diagnosis of tumours[J].JPathol.2007,211(3):286-95.
[28]Cooke S. L.,Ng C. K.,Melnyk N., et al.Genomic analysis of genetic heterogeneityand evolution in high-grade serous ovarian carcinoma[J].Oncogene.2010,29(35):4905-13.
[29]Baba T.,Convery P. A.,Matsumura N., et al.Epigenetic regulation of CD133andtumorigenicity of CD133+ovarian cancer cells[J].Oncogene.2009,28(2):209-18.
[30]Bar J. K.,Harlozinska A.,Popiela A., et al.Expression and mutation of p53in tumoreffusion cells of patients with ovarian carcinoma: response to cisplatin-based chemotherapy[J].Tumour Biol.2001,22(2):83-91.
[31]Rubin S. C.Chemoprevention of hereditary ovarian cancer[J].N Engl J Med.1998,339(7):469-71.
[32]Peng C.,Zhang X.,Yu H.,et al.Wnt5a as a predictor in poor clinical outcome ofpatients and a mediator in chemoresistance of ovarian cancer[J].Int J Gynecol Cancer.2011,21(2):280-8.
[33]Chien J. R.,Aletti G.,Bell D. A.,et al.Molecular pathogenesis and therapeutic targetsin epithelial ovarian cancer[J].J Cell Biochem.2007,102(5):1117-29.
[34]Kurman R. J. and Shih Ie M.The origin and pathogenesis of epithelial ovarian cancer:a proposed unifying theory[J].Am J Surg Pathol.2010,34(3):433-43.
[35]Cheng E. J.,Kurman R. J.,Wang M., et al.Molecular genetic analysis of ovarianserous cystadenomas [J].Lab Invest.2004,84(6):778-84.
[36]Shih Ie M. and Kurman R. J.Ovarian tumorigenesis: a proposed model based onmorphological and molecular genetic analysis[J].Am J Pathol.2004,164(5):1511-8.
[37]Salani R.,Kurman R. J.,Giuntoli R.,2nd, et al.Assessment of TP53mutation usingpurified tissue samples of ovarian serous carcinomas reveals a higher mutation rate thanpreviously reported and does not correlate with drug resistance[J].Int J GynecolCancer.2008,18(3):487-91.
[38]Malpica A.,Deavers M. T.,Lu K., et al.Grading ovarian serous carcinoma using atwo-tier system[J].Am J Surg Pathol.2004,28(4):496-504.
[39]Calatozzolo C.,Gelati M.,Ciusani E., et al.Expression of drug resistance proteins Pgp,MRP1, MRP3, MRP5and GST-pi in human glioma[J].J Neurooncol.2005,74(2):113-21.
[40]Yakirevich E.,Sabo E.,Naroditsky I., et al.Multidrug resistance-related phenotypeand apoptosis-related protein expression in ovarian serous carcinomas[J].Gynecol Oncol.2006,100(1):152-9.
[41]Loo T. W. and Clarke D. M.Mutational analysis of ABC proteins[J].Arch BiochemBiophys.2008,476(1):51-64.
[42]Wu C. P.,Hsieh C. H. and Wu Y. S.The emergence of drug transporter-mediatedmultidrug resistance to cancer chemotherapy[J].Mol Pharm.2011,8(6):1996-2011.
[43]Sharom F. J.The P-glycoprotein multidrug transporter[J].Essays Biochem.2011,50(1):161-78.
[44]Holzmayer T. A.,Hilsenbeck S.,Von Hoff D. D., et al.Clinical correlates of MDR1(P-glycoprotein) gene expression in ovarian and small-cell lung carcinomas[J].J Natl CancerInst.1992,84(19):1486-91.
[45]Han xiaohon G. x., Xue yanjian.On cancer multidrugresistance reversal[J].Journal ofBei Hua University.2005,6(1):36-37.
[46]Kavallaris M.,Leary J.A.,Barrett J.A.,et al.MDR1and multidrug resistance-associated protein (MRP) gene expression in epithelial ovarian tumors[J].Cancer Lett.1996,102(1-2):7-16.
[47]Zhu H.,Wu H.,Liu X., et al.Role of MicroRNA miR-27a and miR-451in theregulation of MDR1/P-glycoprotein expression in human cancer cells[J].Biochem Phar-macol.2008,76(5):582-8.
[48]Lu L.,Katsaros D.,Wiley A., et al.Expression of MDR1in epithelial ovarian cancerand its association with disease progression[J].Oncol Res.2007,16(8):395-403.
[49]Chen H.,Hao J.,Wang L., et al.Coexpression of invasive markers (uPA, CD44) andmultiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancerprogression[J].Br J Cancer.2009,101(3):432-40.
[50]Munoz M.,Henderson M.,Haber M., et al.Role of the MRP1/ABCC1multidrugtransporter protein in cancer[J].IUBMB Life.2007,59(12):752-7.
[51]Kuo T. H.,Liu F. Y.,Chuang C. Y., et al.To predict response chemotherapy usingtechnetium-99m tetrofosmin chest images in patients with untreated small cell lung cancerand compare with p-glycoprotein, multidrug resistance related protein-1, and lungresistance-related protein expression[J].Nucl Med Biol.2003,30(6):627-32.
[52]Yeh J. J.,Hsu N. Y.,Hsu W. H., et al.Comparison of chemotherapy response withP-glycoprotein, multidrug resistance-related protein-1, and lung resistance-related proteinexpression in untreated small cell lung cancer[J].Lung.2005,183(3):177-83.
[53]Ohishi Y.,Oda Y.,Uchiumi T., et al.ATP-binding cassette superfamily transportergene expression in human primary ovarian carcinoma[J].Clin Cancer Res.2002,8(12):3767-75.
[54]Horvath V.,Blanarova O.,Svihalkova-Sindlerova L., et al.Platinum(IV) complex withadamantylamine overcomes intrinsic resistance to cisplatin in ovarian cancer cells[J].GynecolOncol.2006,102(1):32-40.
[55]Ni Z.,Bikadi Z.,Rosenberg M. F., et al.Structure and function of the human breastcancer resistance protein (BCRP/ABCG2)[J].Curr Drug Metab.2010,11(7):603-17.
[56]Lage H. and Dietel M.Effect of the breast-cancer resistance protein on atypicalmultidrug resistance [J].Lancet Oncol.2000,1:169-75.
[57]Ejendal K. F. and Hrycyna C. A.Multidrug resistance and cancer: the role of thehuman ABC transporter ABCG2[J].Curr Protein Pept Sci.2002,3(5):503-11.
[58]Kanzaki A.,Toi M.,Nakayama K., et al.Expression of multidrug resistance-relatedtransporters in human breast carcinoma[J].Jpn J Cancer Res.2001,92(4):452-8.
[59]Maliepaard M.,van Gastelen M. A.,de Jong L. A., et al.Overexpression of theBCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line[J].Cancer Res.1999,59(18):4559-63.
[60]Beeghly A.,Katsaros D.,Chen H., et al.Glutathione S-transferase polymorphisms andovarian cancer treatment and survival[J].Gynecol Oncol.2006,100(2):330-7.
[61]Todo Y.Analysis of p53, MDR-1, and GST-pi expression in endometrialcarcinoma[J].Hokkaido Igaku Zasshi.2003,78(2):117-27.
[62]Cao D. Y.,Shen K.,Yang J. X., et al.The expression of MRP, GST-pi, Topo IIalphaand COX-2in epithelial ovarian cancer and its relationship to drug resistance andprognosis[J].Zhonghua Yi Xue Za Zhi.2007,87(25):1738-41.
[63]Kang S.,Sun H. Y.,Zhou R. M., et al.DNA repair gene associated with clinicaloutcome of epithelial ovarian cancer treated with platinum-based chemotherapy[J].Asian PacJ Cancer Prev.2013,14(2):941-6.
[64]Moxley K. M.,Benbrook D. M.,Queimado L., et al.The role of single nucleotidepolymorphisms of the ERCC1and MMS19genes in predicting platinum-sensitivity,progression-free and overall survival in advanced epithelial ovarian cancer[J].GynecolOncol.2013,130(2):377-82.
[65]Helleman J.,van Staveren I. L.,Dinjens W. N., et al.Mismatch repair and treatmentresistance in ovarian cancer[J].BMC Cancer.2006,6(201).
[66]Scartozzi M.,De Nictolis M.,Galizia E., et al.Loss of hMLH1expression correlateswith improved survival in stage III-IV ovarian cancer patients[J].Eur J Cancer.2003,39(8):1144-9.
[67]Chetrit A.,Hirsh-Yechezkel G.,Ben-David Y., et al.Effect of BRCA1/2mutations onlong-term survival of patients with invasive ovarian cancer: the national Israeli study ofovarian cancer[J].J Clin Oncol.2008,26(1):20-5.
[68]Gourley C.,Michie C. O.,Roxburgh P., et al.Increased incidence of visceralmetastases in scottish patients with BRCA1/2-defective ovarian cancer: an extension of theovarian BRCAness phenotype[J].J Clin Oncol.2010,28(15):2505-11.
[69]Lee S.,Choi E. J.,Jin C., et al.Activation of PI3K/Akt pathway by PTEN reductionand PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cellline[J].Gynecol Oncol.2005,97(1):26-34.
[70]Fraser M.,Leung B. M.,Yan X., et al.p53is a determinant of X-linked inhibitor ofapoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells[J].CancerRes.2003,63(21):7081-8.
[71]Yang J. M.,Vassil A. D. and Hait W. N.Activation of phospholipase C induces theexpression of the multidrug resistance (MDR1) gene through the Raf-MAPK pathway[J].MolPharmacol.2001,60(4):674-80.
[72]焦今文,王蕾,温放等.p38MAPK在不同化疗后卵巢癌中的表达及临床意义[J].中国现代医学杂志.2011,21(15):1828.
[73]Fujita T.,Washio K.,Takabatake D., et al.Proteasome inhibitors can alter the signalingpathways and attenuate the P-glycoprotein-mediated multidrug resistance[J].Int J Cancer.2005,117(4):670-82.
[74]Mackay H. J. and Twelves C. J.Protein kinase C: a target for anticancer drugs[J].Endocr Relat Cancer.2003,10(3):389-96.
[75]卢丹,王志学.卵巢癌组织中多药耐药基因蛋白表达及其临床价值[J].肿瘤防治研究.2004,5:512-514.
[76]金晶,吴绪峰,陈惠祯.P-gp、PKC-α和MRP在上皮性卵巢癌中的表达及其临床意义[J].现代肿瘤医学.2006,14(3):325-329.
[77]Chakrabarty S. and Huang S.Modulation of chemosensitivity in human coloncarcinoma cells by downregulating protein kinase C alpha expression[J].J Exp TherOncol.1996,1(4):218-21.
[78]Masanek U.,Stammler G. and Volm M.Modulation of multidrug resistance in humanovarian cancer cell lines by inhibition of P-glycoprotein170and PKC isoenzymes withantisense oligonucleotides[J].J Exp Ther Oncol.2002,2(1):37-41.
[79]Koti M.,Gooding R. J.,Nuin P., et al.Identification of the IGF1/PI3K/NFkappaB/ERK gene signalling networks associated with chemotherapy resistance andtreatment response in high-grade serous epithelial ovarian cancer[J].BMC Cancer.2013,13:549.
[80]Hung C. C. and Liou H. H.YC-1, a novel potential anticancer agent, inhibitmultidrug-resistant protein via cGMP-dependent pathway[J].Invest New Drugs.2011,29(6):1337-46.
[81]Cao C.,Lu S.,Sowa A., et al.Priming with EGFR tyrosine kinase inhibitor and EGFsensitizes ovarian cancer cells to respond to chemotherapeutical drugs[J].Cancer Lett.2008,266(2):249-62.
[82]L'Esperance S.,Popa I.,Bachvarova M., et al.Gene expression profiling of pairedovarian tumors obtained prior to and following adjuvant chemotherapy: molecular signaturesof chemoresistant tumors[J].Int J Oncol.2006,29(1):5-24.
[83]Chmelarova M.,Krepinska E.,Spacek J., et al.Methylation in the p53promoter inepithelial ovarian cancer[J].Clin Transl Oncol.2013,15(2):160-3.
[84]Kobayashi N.,Abedini M.,Sakuragi N., et al.PRIMA-1increases cisplatin sensitivityin chemoresistant ovarian cancer cells with p53mutation: a requirement for Akt down-regulation[J].J Ovarian Res.2013,6(1):7.
[85]Yang X.,Fraser M.,Moll U. M., et al.Akt-mediated cisplatin resistance in ovariancancer:modulation of p53action on caspase-dependent mitochondrial death pathway[J].Cancer Res.2006,66(6):3126-36.
[86]Materna V.,Surowiak P.,Markwitz E., et al.Expression of factors involved inregulation of DNA mismatch repair-and apoptosis pathways in ovarian cancer patients[J].Oncol Rep.2007,17(3):505-16.
[87]Wang Y. L.,Yan Y. L.,Zhou N. J., et al.Mechanism of multidrug resistance of humansmall cell lung cancer cell line H446/VP[J].Chin Med J (Engl).2010,123(22):3299-303.
[88]Ryan B. M.,O'Donovan N. and Duffy M. J.Survivin: a new target for anti-cancertherapy[J].Cancer Treat Rev.2009,35(7):553-62.
[89]Jiang L.,Luo R. Y.,Yang J., et al.Knockdown of survivin contributes to antitumoractivity in cisplatin-resistant ovarian cancer cells[J].Mol Med Rep.2013,7(2):425-30.
[90]Park S. J.,Armstrong S.,Kim C. H., et al.Lack of EGF receptor contributes to drugsensitivity of human germline cells[J].Br J Cancer.2005,92(2):334-41.
[91]Surowiak P.,Materna V.,Maciejczyk A., et al.Nuclear metallothionein expressioncorrelates with cisplatin resistance of ovarian cancer cells and poor clinical outcome[J].Virchows Arch.2007,450(3):279-85.
[92]Rangel L. B.,Agarwal R.,D'Souza T., et al.Tight junction proteins claudin-3andclaudin-4are frequently overexpressed in ovarian cancer but not in ovariancystadenomas[J].Clin Cancer Res.2003,9(7):2567-75.
[93]Negura L.,Uhrhammer N.,Negura A., et al.Complete BRCA mutation screening inbreast and ovarian cancer predisposition families from a North-Eastern Romanianpopulation[J].Fam Cancer.2010,9(4):519-23.
[94]Pruthi S.,Gostout B. S. and Lindor N. M.Identification and Management of WomenWith BRCA Mutations or Hereditary Predisposition for Breast and Ovarian Cancer[J].MayoClin Proc.2010,85(12):1111-20.
[95]Gallagher D. J.,Konner J. A.,Bell-McGuinn K. M., et al.Survival in epithelialovarian cancer: a multivariate analysis incorporating BRCA mutation status and platinumsensitivity[J].Ann Oncol.2011,22(5):1127-32.
[96]Xu M.,Shao J. and Zeng Y.Molecular classification and molecular targeted therapyof cancer[J].Front Med.2013,7(2):147-9.
[97]Sood A. K. and Buller R. E.Drug resistance in ovarian cancer: from the laboratory tothe clinic[J].Obstet Gynecol.1998,92(2):312-9.
[98]van der Pol M. A.,Broxterman H. J.,Pater J. M., et al.Function of the ABCtransporters, P-glycoprotein, multidrug resistance protein and breast cancer resistance protein,in minimal residual disease in acute myeloid leukemia[J].Haematologica.2003,88(2):134-47.
[99]李晶,吴妙芳,林仲秋.2012NCCN卵巢癌包括输卵管癌和原发腹膜癌临床实践指南（第二版）解读（续）—上皮性卵巢癌[J].国际妇产科学杂志.2012,39(2):315-318.
[100]赵晓东,张毅,杨丽等.复发性卵巢上皮癌"常规化疗药物疗效预测分子靶向化疗"的初步探讨[J].现代妇产科进展.2006,15(4):265-8.
[101]赵晓东,张毅.常规化疗药物疗效预测分子与化疗选药[J].癌症.2006,25(12):1577-80.
[102]Selvakumaran M.,Pisarcik D. A.,Bao R., et al.Enhanced cisplatin cytotoxicity bydisturbing the nucleo-tide excision repair pathway in ovarian cancer cell lines[J].CancerRes.2003,63(6):1311-6.
[103]彭玮丹,张杰,赵永同等.bcl-2核酶(Ribozyme)促进紫杉醇诱导的细胞凋亡[J].中国生物化学与分子生物学报.2000,16(2):258-263.
[104]Zhang T.,Guan M.,Jin H. Y., et al.Reversal of multidrug resistance by smallinterfering double-stranded RNAs in ovarian cancer cells[J].Gynecol Oncol.2005,97(2):501-7.
[105]Rein D. T.,Volkmer A.,Bauerschmitz G., et al.Combination of a MDR1-targetedreplicative adenovirus and chemotherapy for the therapy of pretreated ovarian cancer[J].JCancer Res Clin Oncol.2012,138(4):603-10.
[106]Buller R. E.,Runnebaum I. B.,Karlan B. Y., et al.A phase I/II trial of rAd/p53(SCH58500) gene replacement in recurrent ovarian cancer[J].Cancer Gene Ther.2002,9(7):553-66.
[107]Kumaran G. C.,Jayson G. C. and Clamp A. R.Antiangiogenic drugs in ovariancancer[J].Br J Cancer.2009,100(1):1-7.
[108]Burger R. A.,Sill M. W.,Monk B. J., et al.Phase II trial of bevacizumab in persistentor recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic OncologyGroup Study[J].J Clin Oncol.2007,25(33):5165-71.
[109]Pujade-Lauraine E.,Hilpert F.,Weber B., et al.Bevacizumab Combined WithChemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: The AURELIA Open-LabelRandomized Phase III Trial[J].J Clin Oncol.2014,32(13):1302-8.
[110]Kataria T.,Gupta D.,Bisht S. S., et al.Adaptive Radiotherapy in Lung Cancer:Dosimetric benefits and Clinical outcome[J].Br J Radiol.2014,20130643.
[111]Matei D.,Sill M. W.,Lankes H. A., et al.Activity of sorafenib in recurrent ovariancancer and primary peritoneal carcinomatosis: a gynecologic oncology group trial[J].J ClinOncol.2011,29(1):69-75.
[112]Langdon S. P.,Faratian D.,Nagumo Y., et al.Pertuzumab for the treatment of ovariancancer[J].Expert Opin Biol Ther.2010,10(7):1113-20.
[113]Pautier P.,Joly F.,Kerbrat P., et al.Phase II study of gefitinib in combination withpaclitaxel (P) and carboplatin (C) as second-line therapy for ovarian, tubal or peritonealadenocarcinoma (1839IL/0074)[J].Gynecol Oncol.2010,116(2):157-62.
[114]李蕴潜,赵丽艳,李才.选择性靶向肿瘤干细胞药物的研究现状[J].中国新药杂志.2013,22(24):2903-08.
[115]Schena M.,Shalon D.,Davis R. W., et al.Quantitative monitoring of gene expressionpatterns with a complementary DNA microarray[J].Science.1995,270(5235):467-70.
[116]McCormick M. L.,Gavrila D. and Weintraub N. L.Role of oxidative stress in thepathogenesis of abdominal aortic aneurysms[J].Arterioscler Thromb Vasc Biol.2007,27(3):461-9.
[117]Marchese E.,Vignati A.,Albanese A., et al.Comparative evaluation of genome-widegene expression profiles in ruptured and unruptured human intracranial aneurysms[J].J BiolRegul Homeost Agents.2010,24(2):185-95.
[118]Heller M. J.DNA microarray technology: devices, systems, and applications[J].Annu Rev Biomed Eng.2002,4:129-53.
[119]Subramanian A.,Tamayo P.,Mootha V. K., et al.Gene set enrichment analysis: aknowledge-based approach for interpreting genome-wide expression profiles[J].Proc NatlAcad Sci U S A.2005,102(43):15545-50.
[120]Liu Q.,Dinu I.,Adewale A. J., et al.Comparative evaluation of gene-set analysismethods[J].BMC Bioinformatics.2007,8:431.
[121]Zhang F. and Drabier R.IPAD: the Integrated Pathway Analysis Database forSystematic Enrichment Analysis[J].BMC Bioinformatics.2012,13Suppl15(S7).
[122]Bansal M.,Belcastro V.,Ambesi-Impiombato A., et al.How to infer gene networksfrom expression profiles[J].Mol Syst Biol.2007,3(78).
[123]Hwang S.,Son S. W.,Kim S. C., et al.A protein interaction network associated withasthma[J].J Theor Biol.2008,252(4):722-31.
[124]Ozgur A.,Vu T.,Erkan G., et al.Identifying gene-disease associations using centralityon a literature mined gene-interaction network[J].Bioinformatics.2008,24(13):i277-85.
[125]Raman K.Construction and analysis of protein-protein interaction networks[J].Autom Exp.2010,2(1):2.
[126]Buys T. P.,Chari R.,Lee E. H., et al.Genetic changes in the evolution of multidrugresistance for cultured human ovarian cancer cells[J].Genes Chromosomes Cancer.2007,46(12):1069-79.
[127]Zeller C.,Dai W.,Steele N. L., et al.Candidate DNA methylation drivers of acquiredcisplatin resistance in ovarian cancer identified by methylome and expression profiling[J].Oncogene.2012,31(42):4567-76.
[128]Lavarino C.,Pilotti S.,Oggionni M., et al.p53gene status and response toplatinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma[J].J Clin Oncol.2000,18(23):3936-45.
[129]Moliterni A.,Menard S.,Valagussa P., et al.HER2overexpression and doxorubicin inadjuvant chemotherapy for resectable breast cancer[J].J Clin Oncol.2003,21(3):458-62.
[130]孔北华,W.-x ZHENG.重视卵巢癌的二元论模型与卵巢外起源新说[J].中华妇产科杂志.2011,46(10):721-3.
[131]Plumb J. A.,Strathdee G.,Sludden J., et al.Reversal of drug resistance in humantumor xenografts by2'-deoxy-5-azacytidine-induced demethylation of the hMLH1genepromoter[J]. Cancer Res.2000,60(21):6039-44.
[132]Wiedemeyer W. R.,Beach J. A. and Karlan B. Y.Reversing Platinum Resistance inHigh-Grade Serous Ovarian Carcinoma: Targeting BRCA and the Homologous Recom-bination System[J].Front Oncol.2014,4:34.
[133]Gu J.,Tang Y.,Liu Y., et al.Murine double minute2siRNA and wild-type p53genetherapy enhances sensitivity of the SKOV3/DDP ovarian cancer cell line to cisplatinchemotherapy in vitro and in vivo[J].Cancer Lett.2014,343(2):200-9.
[134]Zeimet A. G. and Marth C.Why did p53gene therapy fail in ovarian cancer[J].Lancet Oncol.2003,4(7):415-22.
[135]Calin G. A.,Sevignani C.,Dumitru C. D., et al.Human microRNA genes arefrequently located at fragile sites and genomic regions involved in cancers[J].Proc Natl AcadSci U S A.2004,101(9):2999-3004.
[136]Lujambio A. and Lowe S. W.The microcosmos of cancer[J].Nature.2012,482(7385):347-55.
[137]Png K. J.,Halberg N.,Yoshida M., et al.A microRNA regulon that mediatesendothelial recruitment and metastasis by cancer cells[J].Nature.2012,481(7380):190-4.
[138]Su X.,Chakravarti D.,Cho M. S., et al.TAp63suppresses metastasis throughcoordinate regulation of Dicer and miRNAs[J].Nature.2010,467(7318):986-90.
[139]Suzuki H. I.,Yamagata K.,Sugimoto K., et al.Modulation of microRNA processingby p53[J].Nature.2009,460(7254):529-33.
[140]Blower P. E.,Verducci J. S.,Lin S., et al.MicroRNA expression profiles for theNCI-60cancer cell panel[J].Mol Cancer Ther.2007,6(5):1483-91.
[141]Blower P. E.,Chung J. H.,Verducci J. S., et al.MicroRNAs modulate thechemosensitivity of tumor cells[J].Mol Cancer Ther.2008,7(1):1-9.
[142]Iida K.,Fukushi J.,Matsumoto Y., et al.miR-125b develops chemoresistance inEwing sarcoma/primitive neuroectodermal tumor[J].Cancer Cell Int.2013,13(1):21.
[143]Bai Y.,Liao H.,Liu T., et al.MiR-296-3p regulates cell growth and multi-drugresistance of human glioblastoma by targeting ether-a-go-go (EAG1)[J].Eur J Cancer.2013,49(3):710-24.
[144]Yang S. M.,Huang C.,Li X. F., et al.miR-21confers cisplatin resistance in gastriccancer cells by regulating PTEN[J].Toxicology.2013,306:162-8.
[145]Hong L.,Yang Z.,Ma J., et al.Function of miRNA in controlling drug resistance ofhuman cancers[J].Curr Drug Targets.2013,14(10):1118-27.
[146]Drayton R. M.,Dudziec E.,Peter S., et al.Reduced Expression of miRNA-27aModulates Cisplatin Resistance in Bladder Cancer by Targeting the Cystine/GlutamateExchanger SLC7A11[J].Clin Cancer Res.2014,20(7):1990-2000.
[147]Murray-Stewart T.,Hanigan C. L.,Woster P. M., et al.Histone deacetylase inhibitionovercomes drug resistance through a miRNA-dependent mechanism[J].Mol Cancer Ther.2013,12(10):2088-99.
[148]Schmittgen T. D.,Lee E. J.,Jiang J., et al.Real-time PCR quantification of precursorand mature microRNA[J].Methods.2008,44(1):31-8.
[149]Castoldi M.,Schmidt S.,Benes V., et al.A sensitive array for microRNA expressionprofiling (miChip) based on locked nucleic acids (LNA)[J].RNA.2006,12(5):913-20.
[150]Maskos U. and Southern E. M.Oligonucleotide hybridizations on glass supports: anovel linker for oligonucleotide synthesis and hybridization properties of oligonucleotidessynthesised in situ[J].Nucleic Acids Res.1992,20(7):1679-84.
[151]Ambros V.The functions of animal microRNAs[J].Nature.2004,431(7006):350-5.
[152]Bartel D. P.MicroRNAs: genomics, biogenesis, mechanism, and function[J].Cell.2004,116(2):281-97.
[153]Du T. and Zamore P. D.microPrimer: the biogenesis and function of microRNA[J].Development.2005,132(21):4645-52.
[154]Zhang B.,Pan X.,Cobb G. P., et al.microRNAs as oncogenes and tumor suppressors[J].Dev Biol.2007,302(1):1-12.
[155]Xu X.Same computational analysis, different miRNA target predictions[J].NatMethods.2007,4(3):191.
[156]Lewis B. P.,Shih I. H.,Jones-Rhoades M. W., et al.Prediction of mammalian micro-RNA targets[J].Cell.2003,115(7):787-98.
[157]Krek A.,Grun D.,Poy M. N., et al.Combinatorial microRNA target predictions[J].Nat Genet.2005,37(5):495-500.
[158]Yang H.,Kong W.,He L., et al.MicroRNA expression profiling in human ovariancancer: miR-214induces cell survival and cisplatin resistance by targeting PTEN[J].CancerRes.2008,68(2):425-33.
[159]Sorrentino A.,Liu C. G.,Addario A., et al.Role of microRNAs in drug-resistantovarian cancer cells[J]. Gynecol Oncol.2008,111(3):478-86.
[160]Kumar S.,Kumar A.,Shah P. P., et al.MicroRNA signature of cis-platin resistant vs.cis-platin sensitive ovarian cancer cell lines[J].J Ovarian Res.2011,4(1):17.
[161]van Jaarsveld M. T.,Helleman J.,Boersma A. W., et al.miR-141regulates KEAP1and modulates cisplatin sensitivity in ovarian cancer cells[J].Oncogene.2013,32(36):4284-93.
[162]Xiang Y.,Ma N.,Wang D., et al.MiR-152and miR-185co-contribute to ovariancancer cells cisplatin sensitivity by targeting DNMT1directly: a novel epigenetic therapyindependent of decitabine[J].Onco-gene.2014,33(3):378-86.
[163]Huh J. H.,Kim T. H.,Kim K., et al.Dysregulation of miR-106a and miR-591conferspaclitaxel resistance to ovarian cancer[J].Br J Cancer.2013,109(2):452-61.
[164]Cittelly D. M.,Dimitrova I.,Howe E. N., et al.Restoration of miR-200c to ovariancancer reduces tumor burden and increases sensitivity to paclitaxel[J].Mol CancerTher.2012,11(12):2556-65.
[165]Yang C.,Cai J.,Wang Q., et al.Epigenetic silencing of miR-130b in ovarian cancerpromotes the development of multidrug resistance by targeting colony-stimulating factor1[J].Gynecol Oncol.2012,124(2):325-34.
[166]Mitamura T.,Watari H.,Wang L., et al.Downregulation of miRNA-31inducestaxane resistance in ovarian cancer cells through increase of receptor tyrosine kinaseMET[J].Onco-genesis.2013,2:e40.
[167]Ruigrok Y. M.,Wijmenga C.,Rinkel G. J., et al.Genomewide linkage in a largeDutch family with intracranial aneurysms: replication of2loci for intracranial aneurysms tochromosome1p36.11-p36.13and Xp22.2-p22.32[J].Stroke.2008,39(4):1096-102.
[168]Feigin V. L. and Findlay M.Advances in subarachnoid hemorrhage[J].Stroke.2006,37(2):305-8.
[169]Juvela S.Natural history of unruptured intracranial aneurysms: risks for aneurysmformation, growth, and rupture[J].Acta Neurochir Suppl.2002,82:27-30.
[170]van der Voet M.,Olson J. M.,Kuivaniemi H., et al.Intracranial aneurysms in Finnishfamilies: confirmation of linkage and refinement of the interval to chromosome19q13.3[J].Am J Hum Genet.2004,74(3):564-71.
[171]Shmulevich I.,Dougherty E. R.,Kim S., et al.Probabilistic Boolean Networks: arule-based uncertainty model for gene regulatory networks[J].Bioinformatics.2002,18(2):261-74.
[172]Chen T.,He H. L. and Church G. M.Modeling gene expression with differentialequations[J].Pac Symp Biocomput.1999:29-40.
[173]Herrero J.,Valencia A. and Dopazo J.A hierarchical unsupervised growing neuralnetwork for clustering gene expression patterns[J].Bioinformatics.2001,17(2):126-36.
[174]Imoto S.,Kim S.,Goto T., et al.Bayesian network and nonparametric heteroscedasticregression for nonlinear modeling of genetic network[J].J Bioinform Comput Biol.2003,1(2):231-52.
[175]Nam S.,Li M.,Choi K., et al.MicroRNA and mRNA integrated analysis (MMIA): aweb tool for examining biological functions of microRNA expression[J].Nucleic AcidsRes.2009,37(Web Server issue):W356-62.
[176]Sales G.,Coppe A.,Bisognin A., et al.MAGIA, a web-based tool for miRNA andGenes Integrated Analysis[J].Nucleic Acids Res.2010,38(Web Server issue):W352-9.
[177]Bisognin A.,Sales G.,Coppe A., et al.MAGIA(2):from miRNA and genes expressiondata integrative analysis to microRNA-transcription factor mixed regulatory circuits (2012update)[J].Nucleic Acids Res.2012,40(Web Server issue):W13-21.
[178]Devaraj S. and Natarajan J.miRNA-mRNA network detects hub mRNAs andcancer specific miRNAs in lung cancer[J].In Silico Biol.2011,11(5-6):281-95.
[179]Zhang W.,Edwards A.,Fan W., et al.miRNA-mRNA correlation-network modules inhuman prostate cancer and the differences between primary and metastatic tumorsubtypes[J].PLoS One.2012,7(6):e40130.
[180]Delfino K. R. and Rodriguez-Zas S. L.Transcription factor-microRNA-target genenetworks associated with ovarian cancer survival and recurrence[J].PLoS One.2013,8(3):e58608.
[1]Jemal A.,Siegel R.,Xu J., et al.Cancer statistics,2010[J].CA Cancer J Clin.2010,60(5):277-300.
[2]Samrao D.,Wang D.,Ough F., et al.Histologic parameters predictive of diseaseoutcome in women with advanced stage ovarian carcinoma treated with neoadjuvantchemotherapy[J].Transl Oncol.2012,5(6):469-74.
[3]Matsuo K.,Eno M. L.,Im D. D., et al.Clinical relevance of extent of extreme drugresistance in epithelial ovarian carcinoma[J].Gynecol Oncol.2010,116(1):61-5.
[4]Bartel D. P.MicroRNAs: genomics, biogenesis, mechanism, and function[J].Cell.2004,116(2):281-97.
[5]Xiang X.,Zhuang X.,Ju S., et al.miR-155promotes macroscopic tumor formation yetinhibits tumor dissemination from mammary fat pads to the lung by preventing EMT[J].Oncogene.2011,30(31):3440-53.
[6]Gao W.,Lu X.,Liu L., et al.MiRNA-21: a biomarker predictive for platinum-basedadjuvant chemotherapy response in patients with non-small cell lung cancer[J].Cancer BiolTher.2012,13(5):330-40.
[7]Aguirre-Gamboa R. and Trevino V.SurvMicro:assessment of miRNA-based prognos-tic signatures for cancer clinical outcomes by multivariate survival analysis[J]. Bioinformatics.2014,30(11):1630-2.
[8]Ahmed F. E.miRNA as markers for the diagnostic screening of colon cancer[J].ExpertRev Anticancer Ther.2014,14(4):463-85.
[9]Carstens J. L.,Lovisa S. and Kalluri R.Microenvironment-dependent cues triggermiRNA-regulated feedback loop to facilitate the EMT/MET switch[J].J Clin Invest.2014,124(4):1458-60.
[10]Drayton R. M.,Dudziec E.,Peter S., et al.Reduced Expression of miRNA-27aModulates Cisplatin Resistance in Bladder Cancer by Targeting the Cystine/GlutamateExchanger SLC7A11[J].Clin Cancer Res.2014,20(7):1990-2000.
[11]Chen Y.,Sun Y.,Chen L., et al.miRNA-200c increases the sensitivity of breast cancercells to doxorubicin through the suppression of E-cadherin-mediated PTEN/Akt signaling[J].Mol Med Rep.2013,7(5):1579-84.
[12]Zhang L.,Pickard K.,Jenei V., et al.miR-153supports colorectal cancer progressionvia pleiotropic effects that enhance invasion and chemotherapeutic resistance[J].Cancer Res.2013,73(21):6435-47.
[13]Sorrentino A.,Liu C. G.,Addario A., et al.Role of microRNAs in drug-resistantovarian cancer cells[J].Gyne-col Oncol.2008,111(3):478-86.
[14]Krek A.,Grun D.,Poy M. N., et al.Combinatorial microRNA target predictions[J].NatGenet.2005,37(5):495-500.
[15]Yang S. M.,Huang C.,Li X. F., et al.miR-21confers cisplatin resistance in gastriccancer cells by regulating PTEN[J].Toxicology.2013,306:162-8.
[16]Medina P. P.,Nolde M. and Slack F. J.OncomiR addiction in an in vivo model ofmicroRNA-21-induced pre-B-cell lymphoma[J].Nature.2010,467(7311):86-90.
[17]Hatley M. E.,Patrick D. M.,Garcia M. R., et al.Modulation of K-Ras-dependent lungtumorigenesis by MicroRNA-21[J].Cancer Cell.2010,18(3):282-93.
[18]Farazi T. A.,Horlings H. M.,Ten Hoeve J. J., et al.MicroRNA sequence andexpression analysis in breast tumors by deep sequencing[J].Cancer Res.2011,71(13):4443-53.
[19]Yao T.,Rao Q.,Liu L., et al.Exploration of tumor-suppressive microRNAs silencedby DNA hypermethy-lation in cervical cancer[J].Virol J.2013,10:175.
[20]Mace T. A.,Collins A. L.,Wojcik S. E., et al.Hypoxia induces the overexpression ofmicroRNA-21in pancreatic cancer cells[J].J Surg Res.2013,184(2):855-60.
[21]Li X.,Lu Y.,Chen Y., et al.MicroRNA profile of paclitaxel-resistant serous ovariancarcinoma based on formalin-fixed paraffin-embedded samples[J].BMC Cancer.2013,13:216.
[22]Wyman S. K.,Parkin R. K.,Mitchell P. S., et al.Repertoire of microRNAs in epithelialovarian cancer as determined by next generation sequencing of small RNA cDNAlibraries[J].PLoS One.2009,4(4):e5311.
[23]Laios A.,O'Toole S.,Flavin R., et al.Potential role of miR-9and miR-223in recurrentovarian cancer[J].Mol Cancer.2008,7:35.
[24]Dahiya N. and Morin P. J.MicroRNAs in ovarian carcinomas[J].Endocr RelatCancer.2010,17(1):F77-89.
[25]Hu X.,Macdonald D. M.,Huettner P. C., et al.A miR-200microRNA cluster asprognostic marker in advanced ovarian cancer[J].Gynecol Oncol.2009,114(3):457-64.
[26]Smith C. M.,Watson D. I.,Leong M. P., et al.miR-200family expression is down-regulated upon neoplastic progression of Barrett's esophagus[J].World J Gastroenterol.2011,17(8):1036-44.
[27]Cochrane D. R.,Howe E. N.,Spoelstra N. S., et al.Loss of miR-200c: A Marker ofAggressiveness and Chemoresistance in Female Reproductive Cancers[J].J Oncol.2010,2010:821717.
[28]Kozaki K.,Imoto I.,Mogi S., et al.Exploration of tumor-suppressive microRNAssilenced by DNA hypermethylation in oral cancer[J].Cancer Res.2008,68(7):2094-105.
[29]Porkka K. P.,Pfeiffer M. J.,Waltering K. K., et al.MicroRNA expression profiling inprostate cancer[J].Cancer Res.2007,67(13):6130-5.
[30]Xiang Y.,Ma N.,Wang D., et al.MiR-152and miR-185co-contribute to ovariancancer cells cisplatin sensitivity by targeting DNMT1directly: a novel epigenetic therapyindependent of decitabine[J].Onco-gene.2014,33(3):378-86.
[1]L'Esperance S.,Popa I.,Bachvarova M., et al.Gene expression profiling of pairedovarian tumors obtained prior to and following adjuvant chemotherapy: molecular signaturesof chemoresistant tumors[J].Int J Oncol.2006,29(1):5-24.
[2]Schena M.,Shalon D.,Davis R. W., et al.Quantitative monitoring of gene expressionpatterns with a complementary DNA microarray[J].Science.1995,270(5235):467-70.
[3]Lisowska K. M.,Olbryt M.,Dudaladava V., et al.Gene expression analysis in ovariancancer faults and hints from DNA microarray study[J].Front Oncol.2014,4:6.
[4]Ng C. F.,Xu J. Y.,Li M. S., et al.Identification of FHL2-regulated genes in liver bymicroarray and bioinformatics analysis[J].J Cell Biochem.2014,115(4):744-53.
[5]Xu Y. C.,Liu Q.,Dai J. Q., et al.Tissue microarray analysis of X-linked inhibitor ofapoptosis (XIAP) expression in breast cancer patients[J].Med Oncol.2014,31(3):764.
[6]Shimizu K. K. and Purugganan M. D.Evolutionary and ecological genomics ofArabidopsis[J].Plant Physiol.2005,138(2):578-84.
[7]高远田.,秦松.植物进化中的正选择作用[J].植物学通报.2008,25(4):401-406.
[8]McCormick M. L.,Gavrila D. and Weintraub N. L.Role of oxidative stress in thepathogenesis of abdominal aortic aneurysms[J].Arterioscler Thromb Vasc Biol.2007,27(3):461-9.
[9]Marchese E.,Vignati A.,Albanese A., et al.Comparative evaluation of genome-widegene expression profiles in ruptured and unruptured human intracranial aneurysms[J].J BiolRegul Homeost Agents.2010,24(2):185-95.
[10]Aznavoorian S.,Murphy A. N.,Stetler-Stevenson W. G., et al.Molecular aspects oftumor cell invasion and metastasis[J].Cancer.1993,71(4):1368-83.
[11]Akiyama S.,Satake N. and Ishioka C.C-kit and other receptor tyrosine kinases play acrucial role in oncogenic signaling and drug-resistance[J].Nihon Rinsho.2012,70Suppl8:36-40.
[12]Chau W. K.,Ip C. K.,Mak A. S., et al.c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/beta-catenin-ATP-bindingcassette G2signaling[J].Onco-gene.2013,32(22):2767-81.
[13]Luo L.,Zeng J.,Liang B., et al.Ovarian cancer cells with the CD117phenotype arehighly tumorigenic and are related to chemotherapy outcome[J].Exp Mol Pathol.2011,91(2):596-602.
[14]Montemurro M. and Bauer S.Treatment of gastrointestinal stromal tumor afterimatinib and sunitinib[J].Curr Opin Oncol.2011,23(4):367-72.
[15]Tanahashi T.,Osada S.,Yamada A., et al.Extracellular signal-regulated kinase and Aktactivation play a critical role in the process of hepatocyte growth factor-inducedepithelial-mesenchymal transition[J].Int J Oncol.2013,42(2):556-64.
[16]Razzak M.Targeted therapies: hepatocyte growth factor-a culprit of drugresistance[J]. Nat Rev Clin Oncol.2012,9(8):429.
[17]Olivero M.,Ruggiero T.,Saviozzi S., et al.Genes regulated by hepatocyte growthfactor as targets to sensitize ovarian cancer cells to cisplatin[J].Mol Cancer Ther.2006,5(5):1126-35.
[18]Saharinen P. and Alitalo K.Double target for tumor mass destruction[J].J Clin Invest.2003,111(9):1277-80.
[19]Bergers G.,Song S.,Meyer-Morse N., et al.Benefits of targeting both pericytes andendothelial cells in the tumor vasculature with kinase inhibitors[J].J Clin Invest.2003,111(9):1287-95.
[20]Shchemelinin I.,Sefc L. and Necas E.Protein kinase inhibitors[J].Folia Biol (Praha).2006,52(4):137-48.
[21]Tian K.,Rajendran R.,Doddananjaiah M., et al.Dynamics of DNA damage inducedpathways to cancer[J].PLoS One.2013,8(9):e72303.
[22]Finn R. S.,Dering J.,Ginther C., et al.Dasatinib, an orally active small moleculeinhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/"triple-negative"breast cancer cell lines growing in vitro[J].Breast Cancer Res Treat.2007,105(3):319-26.
[23]Pichot C. S.,Hartig S. M.,Xia L., et al.Dasatinib synergizes with doxorubicin toblock growth, migration, and invasion of breast cancer cells[J].Br J Cancer.2009,101(1):38-47.
[24]Gomez-Casal R.,Bhattacharya C.,Ganesh N., et al.Non-small cell lung cancer cellssurvived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymaltransition phenotypes[J]. Mol Cancer.2013,12(1):94.
[25]Keshava N.,Gubba S. and Tekmal R. R.Overexpression of macrophage colony-stimulating factor (CSF-1) and its receptor, c-fms, in normal ovarian granulosa cells leads tocell proliferation and tumorigenesis[J].J Soc Gynecol Investig.1999,6(1):41-9.
[26]Toy E. P.,Azodi M.,Folk N. L., et al.Enhanced ovarian cancer tumorigenesis andmetastasis by the macrophage colony-stimulating factor[J].Neoplasia.2009,11(2):136-44.
[27]Chambers S. K.Role of CSF-1in progression of epithelial ovarian cancer[J].FutureOncol.2009,5(9):1429-40.
[28]Abi Saab W. F.,Brown M. S. and Chadee D. N.MLK4beta functions as a negativeregulator of MAPK signaling and cell invasion[J].Oncogenesis.2012,1:e6.
[29]Narayan G.,Freddy A. J.,Xie D., et al.Promoter methylation-mediated inactivation ofPCDH10in acute lymphoblastic leukemia contributes to chemotherapy resistance[J].GenesChromosomes Cancer.2011,50(12):1043-53.
[30]Ding K.,Su Y.,Pang L., et al.Inhibition of apoptosis by downregulation of hBex1, anovel mechanism, contributes to the chemoresistance of Bcr/Abl+leukemic cells[J].Carcinogenesis.2009,30(1):35-42.
[31]Rikiyama T.,Curtis J.,Oikawa M., et al.GCF2: expression and molecular analysis ofrepression[J]. Biochim Biophys Acta.2003,1629(1-3):15-25.
[32]Li J. P.,Cao N. X.,Jiang R. T., et al.Knockdown of GCF2/LRRFIP1by RNAi CausesCell Growth Inhibition and Increased Apoptosis in Human Hepatoma HepG2Cells[J].AsianPac J Cancer Prev.2014,15(6):2753-8.
[33]Yang W.,He M.,Zhao J., et al.Association of ITGA3gene polymorphisms withsusceptibility and clinicopathological characteristics of osteosarcoma[J].Med Oncol.2014,31(2):826.
[34]Ibrahim S. A.,Yip G. W.,Stock C., et al.Targeting of syndecan-1by microRNAmiR-10b promotes breast cancer cell motility and invasiveness via a Rho-GTPase-andE-cadherin-dependent mechanism[J].Int J Cancer.2012,131(6):E884-96.
[1]Ruigrok Y. M.,Wijmenga C.,Rinkel G. J., et al.Genomewide linkage in a large Dutchfamily with intracranial aneurysms: replication of2loci for intracranial aneurysms tochromosome1p36.11-p36.13and Xp22.2-p22.32[J].Stroke.2008,39(4):1096-102.
[2]Nam S.,Li M.,Choi K., et al.MicroRNA and mRNA integrated analysis (MMIA): aweb tool for examining biological functions of microRNA expression[J].Nucleic AcidsRes.2009,37(Web Server issue):W356-62.
[3]Sales G.,Coppe A.,Bisognin A., et al.MAGIA, a web-based tool for miRNA and GenesIntegrated Analysis[J].Nucleic Acids Res.2010,38(Web Server issue):W352-9.
[4]Bisognin A.,Sales G.,Coppe A., et al.MAGIA(2): from miRNA and genes expressiondata integrative analysis to microRNA-transcription factor mixed regulatory circuits (2012update)[J].Nucleic Acids Res.2012,40(Web Server issue):W13-21.
[5]Saito R.,Smoot M. E.,Ono K., et al.A travel guide to Cytoscape plugins[J].NatMethods.2012,9(11):1069-76.
[6]Feigin V. L. and Findlay M.Advances in subarachnoid hemorrhage[J].Stroke.2006,37(2):305-8.
[7]Juvela S.Natural history of unruptured intracranial aneurysms: risks for aneurysmformation, growth, and rupture[J].Acta Neurochir Suppl.2002,82(27-30.
[8]van der Voet M.,Olson J. M.,Kuivaniemi H., et al.Intracranial aneurysms in Finnishfamilies: confirmation of linkage and refinement of the interval to chromosome19q13.3[J].Am J Hum Genet.2004,74(3):564-71.
[9]Hu X.,Macdonald D. M.,Huettner P. C., et al.A miR-200microRNA cluster asprognostic marker in advanced ovarian cancer[J].Gynecol Oncol.2009,114(3):457-64.
[10]Smith C. M.,Watson D. I.,Leong M. P., et al.miR-200family expression isdown-regulated upon neoplastic progression of Barrett's esophagus[J].World JGastroenterol.2011,17(8):1036-44.
[11]Sun Y.,Shen S.,Liu X., et al.miR-429inhibits cells growth and invasion and regulatesEMT-related marker genes by targeting Onecut2in colorectal carcinoma[J].Mol Cell Biochem.2014,390(12):19-30.
[12]Cochrane D. R.,Howe E. N.,Spoelstra N. S., et al.Loss of miR-200c: A Marker ofAggressiveness and Chemoresistance in Female Reproductive Cancers[J].J Oncol.2010:1-12.
[13]Hapkova I.,Skarda J.,Rouleau C., et al.High expression of the RNA-binding proteinRBPMS2in gastrointestinal stromal tumors[J].Exp Mol Pathol.2013,94(2):314-21.
[14]Skawran B.,Steinemann D.,Becker T., et al.Loss of13q is associated with genesinvolved in cell cycle and proliferation in dedifferentiated hepatocellular carcinoma[J].ModPathol.2008,21(12):1479-89.
[15]Gentles A. J.,Plevritis S. K.,Majeti R., et al.Association of a leukemic stem cell geneexpression signature with clinical outcomes in acute myeloid leukemia[J].JAMA.2010,304(24):2706-15.
[16]Xu X.,Patrakka J.,Sistani L., et al.Expression of novel podocyte-associated proteinssult1b1and ankrd25[J].Nephron Exp Nephrol.2011,117(2):e39-46.
[17]Kozaki K.,Imoto I.,Mogi S., et al.Exploration of tumor-suppressive microRNAssilenced by DNA hypermethylation in oral cancer[J].Cancer Res.2008,68(7):2094-105.
[18]Arai K.,Sakamoto R.,Kubota D., et al.Proteomic approach toward molecularbackgrounds of drug resistance of osteosarcoma cells in spheroid culturesystem[J].Proteomics.2013,13(15):2351-60.
[19]Cho H. J.,Baek K. E.,Kim I. K., et al.Proteomics-based strategy to delineate themolecular mechanisms of RhoGDI2-induced metastasis and drug resistance in gastriccancer[J]. J Proteome Res.2012,11(4):2355-64.
[20]Tang S.,Huang W.,Zhong M., et al.Identification Keratin1as a cDDP-resistantprotein in nasopharyngeal carcinoma cell lines[J].J Proteomics.2012,75(8):2352-60.
[21]Osmak M.,Niksic D.,Brozovic A., et al.Drug resistant tumor cells have increasedlevels of tumor markers for invasion and metastasis[J].Anticancer Res.1999,19(4B):3193-7.
[22]Sagulenko V.,Muth D.,Sagulenko E., et al.Cathepsin D protects humanneuroblastoma cells from doxorubicin-induced cell death[J].Carcinogenesis.2008,29(10):1869-77.
[23]Unsicker K.,Spittau B. and Krieglstein K.The multiple facets of the TGF-beta familycytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1[J].CytokineGrowth Factor Rev.2013,24(4):373-84.
[24]Mimeault M.,Johansson S. L. and Batra S. K.Marked improvement of cytotoxiceffects induced by docetaxel on highly metastatic and androgen-independent prostate cancercells by downregulating macrophage inhibitory cytokine-1[J].Br J Cancer.2013,108(5):1079-91.
[25]Barderas R.,Mendes M.,Torres S., et al.In-depth characterization of the secretome ofcolorectal cancer metastatic cells identifies key proteins in cell adhesion, migration, andinvasion[J].Mol Cell Proteomics.2013,12(6):1602-20.
[26]Rotkrua P.,Akiyama Y.,Hashimoto Y., et al.MiR-9downregulates CDX2expressionin gastric cancer cells[J].Int J Cancer.2011,129(11):2611-20.
[27]Uhlmann S.,Zhang J. D.,Schwager A., et al.miR-200bc/429cluster targetsPLCgamma1and differentially regulates proliferation and EGF-driven invasion thanmiR-200a/141in breast cancer[J].Oncogene.2010,29(30):4297-306.
[28]Adam L.,Zhong M.,Choi W., et al.miR-200expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growthfactor receptor therapy[J].Clin Cancer Res.2009,15(16):5060-72.
[29]Tang H.,Liu X.,Wang Z., et al.Interaction of hsa-miR-381and glioma suppressorLRRC4is involved in glioma growth[J].Brain Res.2011,1390:21-32.
[30]Papp G.,Krausz T.,Stricker T. P., et al.SMARCB1expression in epithelioid sarcomais regulated by miR-206, miR-381, and miR-671-5p on Both mRNA and proteinlevels[J].Genes Chromosomes Cancer.2014,53(2):168-76.
[31]Wu X. M.,Shao X. Q.,Meng X. X., et al.Genome-wide analysis of microRNA andmRNA expression signatures in hydroxycamptothecin-resistant gastric cancer cells[J].ActaPharmacol Sin.2011,32(2):259-69.
[32]Izquierdo J. M.,Alcalde J.,Carrascoso I., et al.Knockdown of T-cell intracellularanti-gens triggers cell proliferation, invasion and tumour growth[J].Biochem J.2011,435(2):337-44.
[33]Zhang L.,Volinia S.,Bonome T., et al.Genomic and epigenetic alterations deregulatemicroRNA expression in human epithelial ovarian cancer[J].Proc Natl Acad Sci U S A.2008,105(19):7004-9.
[34]Hwang-Verslues W. W.,Chang P. H.,Wei P. C., et al.miR-495is upregulated by E12/E47in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance viadownregulation of E-cadherin and REDD1[J].Oncogene.2011,30(21):2463-74.
[35]Trueb B.,Zhuang L.,Taeschler S., et al.Characterization of FGFRL1, a novelfibroblast growth factor (FGF) receptor preferentially expressed in skeletal tissues[J].J BiolChem.2003,278(36):33857-65.
[36]Schild C. and Trueb B.Aberrant expression of FGFRL1, a novel FGF receptor, inovarian tumors[J].Int J Mol Med.2005,16(6):1169-73.
[37]Xu Y.,Ohms S. J.,Li Z., et al.Changes in the expression of miR-381and miR-495areinversely associated with the expression of the MDR1gene and development of multi-drugresistance[J].PLoS One.2013,8(11):e82062.
[38]Shih K. K.,Qin L. X.,Tanner E. J., et al.A microRNA survival signature (MiSS) foradvanced ovarian cancer[J].Gynecol Oncol.2011,121(3):444-50.
[39]Liguori L.,Andolfo I.,de Antonellis P., et al.The metallophosphodiesterase Mpped2impairs tumorigenesis in neuroblastoma[J].Cell Cycle.2012,11(3):569-81.
[40]Song B.,Wang Y.,Xi Y., et al.Mechanism of chemoresistance mediated by miR-140in human osteosarcoma and colon cancer cells[J].Oncogene.2009,28(46):4065-74.
[41]Hummel R.,Wang T.,Watson D. I., et al.Chemotherapy-induced modification ofmicroRNA expression in esophageal cancer[J].Oncol Rep.2011,26(4):1011-7.