Research Paper Volume 11, Issue 18 pp 7357—7385
miR-375-3p suppresses tumorigenesis and partially reverses chemoresistance by targeting YAP1 and SP1 in colorectal cancer cells
- 1 School of Medicine, Southeast University, Nanjing 210009, China
- 2 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
- 3 Department of Laboratory Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
Received: May 5, 2019 Accepted: August 13, 2019 Published: September 22, 2019
https://doi.org/10.18632/aging.102214How to Cite
Copyright © 2019 Xu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Clinically, one of the principal factors in the failure of advanced colorectal cancer (CRC) treatment is chemoresistance to 5-fluorouracil (5FU)-based chemotherapy. Although microRNA-375-3p (miR-375) is considered a tumor suppressor in multiple cancers, the mechanism of miR-375 in the regulation of drug resistance in CRC remains unclear. In this study, we investigated the chemosensitivity of miR-375 to 5FU in CRC from biological and clinical aspects. We found that miR-375 was significantly downregulated in CRC tissues and cell lines, and low miR-375 expression was strongly correlated with poor overall survival in CRC patients. Overexpression of miR-375 sensitized CRC cells to a broad spectrum of chemotherapeutic drugs in vitro and in vivo. Further mechanistic analysis demonstrated that miR-375 enhanced CRC cell sensitivity to 5FU by directly targeting YAP1 and SP1. MiR-375 downregulated YAP1, resulting in reduced expression of the Hippo-YAP1 pathway downstream genes CTGF, cyclin D1 and BIRC5 (also known as survivin). Overall, miR-375 was confirmed as a prospective molecular biomarker in the chemoresistance and prognosis of CRC patients, and the synergy between miR-375 and chemotherapeutic drugs could be a promising therapeutic strategy for CRC patients, especially with chemoresistance.