title: miR-663 overexpression induced by endoplasmic reticulum stress modulates hepatocellular carcinoma cell apoptosis via transforming growth factor beta 1.
abstract: microRNAs are commonly dysregulated in a number of human cancers, for example, hepatocellular carcinoma (HCC), but the precise mechanism of dysregulation has not been extensively studied. Although previous studies have indicated that HCC cells are resistant to endoplasmic reticulum (ER) stress-induced apoptosis, little is known about the relationship between microRNAs and ER stress-mediated apoptosis resistance. In this study, we have demonstrated for the first time that the expression level of miR-663 was significantly upregulated in HCC cells co-incubated with tunicamycin, an ER stress inducer, as measured by a microRNA-chromatin immunoprecipitation microarray and quantitative real-time polymerase chain reaction; however, the effect of miR-663 on HCC cell apoptosis remains unknown. To investigate the potential involvement of miR-663 in HCC, HepG2 cells were transfected with mimics or inhibitors of miR-663. Consequently, we identified that downregulation of miR-663 suppressed HCC cell proliferation and promoted apoptosis under ER stress. Target gene analysis further predicted that the effects of miR-663 on HCC cells were mediated by directly targeting transforming growth factor beta 1 (TGFB1). Interestingly, the expression levels of TGFB1 changed inversely after downregulation or upregulation of miR-663 by inhibitors or mimics of miR-663 in HepG2 cells. Additionally, TGFB1 knockdown inhibited apoptosis in HepG2 cells. In sum, our study identifies a role for miR-663 as a critical regulator of ER stress-mediated apoptosis resistance in HCC cells via TGFB1. Accordingly, therapies aimed at the miR-663/TGFB1 axis might represent a hopeful strategy to overcome apoptosis resistance in HCC.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Jiatao
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Hanqing
authors.initials: H
authors.lastname: Yu
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Sun
keywords: TGFB1; apoptosis; endoplasmic reticulum stress; hepatocellular carcinoma cells; miR-663; microRNAs