Lv L, Deng H, Li Y, Zhang C, Liu X, Liu Q, Zhang D, Wang L, Pu Y, Zhang H, He Y, Wang Y, Yu Y, Yu T, Zhu J
Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China.
Department of Biology, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, China.
Cell Death Dis. 2014 Sep 4;5(9):e1402. doi: 10.1038/cddis.2014.367.
Chemoresistance hinders the curative cancer chemotherapy. To define the role of the DNA methylation-regulated microRNA (miR) genes in the chemoresistance of bladder cancer, we performed both DNA methylomic and miRomic analyses of a multi-chemosensitive (5637) versus a multi-chemoresistant (H-bc) cell line and found that miR-193a-3p is hypermethylated/silenced in 5637 and hypomethylated/expressed in H-bc cells. A forced reversal of its level turned around the chemoresistance in the cultured cells and the tumor xenografts in nude mice. Three of its targets: SRSF2, PLAU and HIC2, work in concert to relay the miR-193a-3p's impact on the bladder cancer chemoresistance by modulating the activities of the following five signaling pathways: DNA damage, Notch, NF-κB, Myc/Max, and Oxidative Stress. In addition to the mechanistic insights in how the newly identified miR-193a-3p/SRSF2,PLAU,HIC2/five signaling pathway axis regulates the chemoresistance of bladder cancer cells, our study provides a new set of diagnostic targets for the guided personalized chemotherapy of bladder cancer.
化疗耐药阻碍了癌症化疗的治愈效果。为了明确DNA甲基化调控的微小RNA（miR）基因在膀胱癌化疗耐药中的作用，我们对多药敏感（5637）和多药耐药（H-bc）细胞系进行了DNA甲基化组和miR组分析，发现miR-193a-3p在5637细胞中发生高甲基化/沉默，而在H-bc细胞中发生低甲基化/表达。其水平的强制逆转改变了培养细胞和裸鼠肿瘤异种移植模型中的化疗耐药情况。它的三个靶标：SRSF2、PLAU和HIC2，协同作用，通过调节以下五个信号通路的活性来传递miR-193a-3p对膀胱癌化疗耐药的影响：DNA损伤、Notch、NF-κB、Myc/Max和氧化应激。除了新发现的miR-193a-3p/SRSF2、PLAU.HIC2/五个信号通路轴如何调节膀胱癌细胞化疗耐药的机制性见解外，我们的研究还为膀胱癌的导向性个体化化疗提供了一组新的诊断靶点。
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