miR-3656 expression enhances the chemosensitivity of pancreatic cancer to gemcitabine through modulation of the RHOF/EMT axis.
miR-3656 expression enhances the chemosensitivity of pancreatic cancer to gemcitabine through modulation of the RHOF/EMT axis.
复制标题
DOI：
10.1038/cddis.2017.530
复制
发表时间：
2017-10-19
影响因子：
9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Yang RM;Zhan M;Xu SW;Long MM;Yang LH;Chen W;Huang S;Liu Q;Zhou J;Zhu J;Wang J
胰腺癌对化疗药物的高度难治性是导致其预后不良的主要原因之一。microRNA（miRNAs）是基因表达的关键调节因子，并参与了从癌症发展到耐药性的各种过程。在此，通过吉西他滨耐药（GR）和亲本PANC-1细胞系的miRNA谱分析，我们发现GR PANC-1细胞中miR-3656的一致减少。miR-3656过表达增强了吉西他滨的抗肿瘤作用，而miR-3656的沉默导致相反的作用。通过使用体外和体内模型进行机制研究，我们发现miR-3656可以靶向RHOF，小GTP酶Rho亚家族的成员，并调节EMT过程。此外，通过TWIST 1过表达的EMT进展损害了miR-3656的化疗增强作用。最后，我们发现与邻近的非癌胰腺组织相比，PC组织中miR-3656的水平显著降低，RHOF的水平显著升高，这也与PC患者的预后不良有关。综上所述，我们的研究结果表明，miR-3656/RHOF/EMT轴是参与调节PC GR的重要因素，并强调了基于miR-3656的新型临床模式作为PC患者治疗方法的潜力。
The highly refractory nature of pancreatic cancer (PC) to chemotherapeutic drugs is one of the key reasons contributing to the poor prognosis of this disease. MicroRNAs (miRNAs) are key regulators of gene expression and have been implicated in a variety of processes from cancer development through to drug resistance. Herein, through miRNA profiling of gemcitabine-resistant (GR) and parental PANC-1 cell lines, we found a consistent reduction of miR-3656 in GR PANC-1 cells. miR-3656 overexpression enhanced the antitumor effect of gemcitabine, whereas silencing of miR-3656 resulted in the opposite effect. By performing mechanistic studies using both in vitro and in vivo models, we found that miR-3656 could target RHOF, a member of the Rho subfamily of small GTPases, and regulate the EMT process. Moreover, enforced EMT progression via TWIST1 overexpression compromised the chemotherapy-enhancing effects of miR-3656. Finally, we found significantly lower levels of miR-3656 and higher levels of RHOF in PC tissues compared with adjacent noncancerous pancreatic tissues, and this was also associated with poor PC patients’ prognosis. Taken together, our results suggest that the miR-3656/RHOF/EMT axis is an important factor involved in regulating GR in PC, and highlights the potential of novel miR-3656-based clinical modalities as a therapeutic approach in PC patients.
登录
查看更多内容
影响因子：
9
作者：
通讯作者：
--
GEPIA：用于癌症和正常基因表达谱和交互式分析的网络服务器。
影响因子：
14.9
作者：
Tang Z;Li C;Kang B;Gao G;Li C;Zhang Z
通讯作者：
Zhang Z
影响因子：
64.8
作者：
Fischer KR;Durrans A;Lee S;Sheng J;Li F;Wong ST;Choi H;El Rayes T;Ryu S;Troeger J;Schwabe RF;Vahdat LT;Altorki NK;Mittal V;Gao D
通讯作者：
Gao D
DOI：
10.1038/nrclinonc.2017.44
发表时间：
2017-10
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Shibue T;Weinberg RA
通讯作者：
Weinberg RA
影响因子：
8
作者：
Bellovin, D. I.;Simpson, K. J.;Mercurio, A. M.
通讯作者：
Mercurio, A. M.