The network of DAB2IP-miR-138 in regulating drug resistance of renal cell carcinoma associated with stem-like phenotypes.
The network of DAB2IP-miR-138 in regulating drug resistance of renal cell carcinoma associated with stem-like phenotypes.
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DOI：
10.18632/oncotarget.17756
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发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Hsieh JT
中科院分区：
文献类型：
--
作者：
Yun EJ;Zhou J;Lin CJ;Xu S;Santoyo J;Hernandez E;Lai CH;Lin H;He D;Hsieh JT
靶向治疗是转移性肾细胞癌（RCC）的标准治疗方法，但反应率并不高，由于治疗耐药性的出现，只能延长患者的短暂生存期。虽然机制尚不完全清楚，但癌症起始细胞（CIC）的存在可能是耐药的基础。然而，在RCC中识别CIC表型及其生物标志物似乎是多种多样的，并且从许多报道中存在争议。在这项研究中，我们采用了不同的方法来关注RCC- cic的调控机制，并揭示了dab2ip介导的miR-138表达，该表达通过靶向ABC转运蛋白（ABCA13）和致癌组蛋白甲基转移酶EZH2在RCC中调节茎样表型中起关键作用，而RCC中miR-138基因表达的下调是由于DNA甲基转移酶1 （DNMT1）沉默表观遗传基因。我们还描述了RCC-CIC中ABCA13促进其耐药和耐药的个体机制。EZH2维持茎样表型。值得注意的是，ABCA13和EZH2的表达升高与RCC患者的总生存率相关，可作为潜在的预后指标。综上所述，本研究证明了dab2ip介导的miR-138在RCC进展过程中调节CIC表型的有效而独特的途径，也为靶向耐药RCC提供了新的治疗策略。
Targeted therapy is a standard of care for metastatic renal cell carcinoma (RCC) but the response rate is not overwhelmed, which only prolongs a short survival of patients due to the onset of therapeutic resistance. Although the mechanisms are not fully understood, the presence of cancer initiating cells (CIC) may underlie the drug resistance. Nevertheless, identifying CIC phenotypes with its biomarkers in RCC appear to be diverse and controversial from many reports. In this study, we took a different approach to focus on the regulatory mechanism in RCC-CIC and unveil DAB2IP-mediated miR-138 expression that plays a critical role in modulating stem-like phenotypes in RCC via targeting the ABC transporter (ABCA13) as well as oncogenic histone methyltransferase EZH2 while down regulation of miR-138 gene expression in RCC is due to epigenetic gene silencing by DNA methyltransferase 1 (DNMT1). We also characterize the individual mechanism by which ABCA13 in RCC-CIC contributes to its drug resistance and. EZH2 maintain stem-like phenotypes. Noticeably, elevated expression of ABCA13 and EZH2 is correlated with overall survival of RCC patients, which can be used as potential prognostic markers. Taken together, this study demonstrates a potent and unique pathway of DAB2IP-mediated miR-138 in modulating CIC phenotypes during RCC progression and also offers a new therapeutic strategy of targeting drug resistant RCC.
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影响因子：
37.3
作者：
Nymoen DA;Holth A;Hetland Falkenthal TE;Tropé CG;Davidson B
通讯作者：
Davidson B
EZH2 表达和活性在肾细胞癌中的预后价值：一项前瞻性研究
影响因子：
3.7
作者：
Liu L;Xu Z;Zhong L;Wang H;Jiang S;Long Q;Xu J;Guo J
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Guo J
影响因子：
5.1
作者：
Li, Ming;Wang, Ying;Wu, Bin
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Wu, Bin
影响因子：
4.8
作者：
Bussolati, Benedetta;Bruno, Stefania;Camussi, Giovanni
通讯作者：
Camussi, Giovanni
影响因子：
8
作者：
Hildebrandt, M. A. T.;Gu, J.;Wu, X.
通讯作者：
Wu, X.