The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression.
The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression.
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DNA甲基化调节的miR-193a-3p通过抑制SRSF2/PLAU/HIC2表达来决定膀胱癌的多重化疗耐药性
DOI：
10.1038/cddis.2014.367
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发表时间：
2014-09-04
影响因子：
9
通讯作者：
Zhu J
中科院分区：
文献类型：
--
作者：
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
化疗耐药性阻碍了癌症化疗的有效性。为了确定DNA甲基化调节的microRNA（miR）基因在膀胱癌的化学抗性中的作用，我们对多化学敏感（5637）与多化学抗性（H-bc）细胞系进行了DNA甲基化组学和miRomic分析，发现miR-193 a-3 p在5637中高甲基化/沉默，在H-bc细胞中低甲基化/表达。其水平的强制逆转逆转了培养细胞和裸鼠肿瘤异种移植物中的化学抗性。它的三个目标：SRSF 2、PLAU和miR-193 a-3 p通过调节以下五个信号通路的活性协同工作来传递miR-193 a-3 p对膀胱癌化学抗性的影响：DNA损伤、Notch、NF-κB、Myc/Max和氧化应激。除了新发现的miR-193 a-3 p/SRSF 2、PLAU、miR-193 a-3 p/five信号通路轴如何调节膀胱癌细胞的化疗耐药性的机制见解外，我们的研究为膀胱癌的指导个性化化疗提供了一组新的诊断靶点。
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.