MiR-3656 expression enhances the chemosensitivity of pancreatic cancer to gemcitabine through modulation of the RHOF/EMT axis

Rui-Meng Yang,Jian Wang,Lin-Hua Yang,Man-Mei Long,Ming Zhan,Jun Zhou,Jun Zhu,Sun-Wang Xu,Wei Chen,Shuai Huang,Qiang Liu

doi:10.1038/cddis.2017.530

Abstract

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.

Highlights

Owing to our current inability to detect the disease in its early stages, most diagnosed patients miss the opportunity for curative surgery.[3]
Gemcitabine-based chemotherapy forms the first-line treatment for PC,[5] drug resistance, either intrinsic or acquired, compromises therapeutic efficacy and represents a significant challenge for the treatment of PC.[6,7]. Several characteristics such as, epithelial-to-mesenchymal transition (EMT) and the accumulation of cancer stem cells have been suggested as important contributors to PC chemoresistance,[8,9] the precise molecular mechanisms remain largely unknown
When combined with two other expression profiles from gene expression omnibus (GEO) databases (GSE80616 and GSE79234), we found that miR-3656 was the only miRNA commonly reduced in all PANC-1-GR cell lines (Figures 1b-d)

Summary

Introduction

Owing to our current inability to detect the disease in its early stages, most diagnosed patients miss the opportunity for curative surgery.[3]. EMT is a common feature of various types of tumors During this process, cancer cells gradually lose expression of epithelial markers and instead, acquire the mesenchymal cell features required for further migration and invasion.[15] Interestingly, recent evidence suggests that the EMT process is tightly correlated with drug resistance.[16,17] Mouse PC models deficient in EMT-inducing transcription factors, such as TWIST1, Snail and ZEB1, reveal enhanced gemcitabine sensitivity and increased overall survival rates.[17,18,19] Signaling pathways such as TGF-β, Wnt and Notch have been. Our data provide new direction for the future development of potential molecularly targeted therapies in achieving improved therapeutic outcomes for PC patients

Methods

Results

Conclusion