MiR-143-5p Deficiency Triggers EMT and Metastasis by Targeting HIF-1α in Gallbladder Cancer

Abstract

Background/Aims: Early metastasis plays a pivotal role in tumor-caused death in gallbladder cancer (GBC) patients. Increasing evidence suggest that miR-143-5p is an active player involved in cancer metastasis and a potential therapeutic target. However, its role in the development of GBC cells remains unclear. The aim of this study is to reveal the inhibiting effects of miR-143-5p on the proliferation and metastasis in GBC. Methods: Quantitative real-time PCR were used to investigate miR-143-5p and its target HIF-1α mRNA levels. Protein expression was measured by immunohistochemistry and western blot. The function and regulation mechanism of miR-143-5p was confirmed by MTS, colony formation, wound healing, transwell, and luciferase reporter assays. Results: miR-143-5p was first found significantly reduced in GBC tissues compared with corresponding noncancerous gallbladder tissues. In addition, miR-143-5p deficiency correlated well with larger tumor size, advanced TNM stage, and poorer survival rate. In vitro, miR-143-5p addition dramatically suppressed GBC cells proliferation, migration and invasion, whereas miR-143-5p antisense led the opposite effects. Further elucidating the molecular mechanism inside, we found miR-143-5p exerted its inhibitory function through downregulating the expression of HIF-1α, which further reduced Twist1 and impeded epithelial-mesenchymal transition (EMT). Conclusions: Altogether, our studies identified a novel regulator, miR-143-5p, implicated in GBC prognosis through targeting HIF-1α/EMT related signaling pathway, which could serve as a biomarker and therapeutic target for GBC.

Keywords

• Gallbladder cancer
• miR-143-5p
• HIF-1α
• Epithelial-mesenchymal transition
• Metastasis