CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Cell Death Dis. 2017 Oct 19;8(10):e3129. doi: 10.1038/cddis.2017.530.
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.
胰腺癌（PC）对化疗药物的高度耐药性是导致这种疾病预后不良的关键原因之一。microRNAs（miRNAs）是基因表达的关键调节剂，参与了从癌症发展到耐药性的多种过程。在此，通过对吉西他滨耐药（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 的表达一致降低。miR-3656 的过表达增强了吉西他滨的抗肿瘤作用，而 miR-3656 的沉默则产生了相反的效果。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 Rho 家族小 GTPase 亚家族的成员 RHOF，并调节 EMT 过程。此外，通过 TWIST1 过表达强制 EMT 进展削弱了 miR-3656 的化疗增强作用。最后，我们发现与相邻非癌性胰腺组织相比，PC 组织中的 miR-3656 水平明显降低，RHOF 水平升高，这也与 PC 患者的不良预后相关。总之，我们的研究结果表明，miR-3656/RHOF/EMT 轴是调节 PC 中 GR 的一个重要因素，并强调了基于新型 miR-3656 的临床方法作为 PC 患者治疗方法的潜力。
