J Cancer 2020; 11(21):6188-6203. doi:10.7150/jca.45998 This issue

Research Paper

High-matrix-stiffness induces promotion of hepatocellular carcinoma proliferation and suppression of apoptosis via miR-3682-3p-PHLDA1-FAS pathway

Bowen Yao1,*, Yongshen Niu1,*, Yazhao Li2, Tianxiang Chen1, Xinyu Wei3, Qingguang Liu1,✉

1. Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China
2. Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, China
3. Medicine college, Xi'an Jiaotong University, No. 76 Yanta West Road, Xi'an 710061, China
* Author contributed equally

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Citation:
Yao B, Niu Y, Li Y, Chen T, Wei X, Liu Q. High-matrix-stiffness induces promotion of hepatocellular carcinoma proliferation and suppression of apoptosis via miR-3682-3p-PHLDA1-FAS pathway. J Cancer 2020; 11(21):6188-6203. doi:10.7150/jca.45998. Available from https://www.jcancer.org/v11p6188.htm

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Abstract

Hepatocellular carcinoma (HCC) with malignant behaviors related to death causes distant metastasis and is the fourth primary cancer in the whole world, which has taken millions lives in Asian countries such as China. The novel miR-3682-3p involving high-expression-related poor prognosis in HCC tissues and cell lines indicate oncogenesis functions in vitro and in vivo. According to TCGA database, our group find several none-coding RNAs showing abnormal expression including miR-3682-3p, thus we originally confirmed the inhibition of proliferation and acceleration of apoptosis are enhanced in miR-3682-3p knock-down cell lines. Then, in nude mice transplantation assays, we found the suppressor behaviors, smaller nodules and lower speed of tumor expansion in model of injection of cell cultured and transfected shRNA-miR-3682-3p. A combination of databases (Starbase, Targetscan and MiRgator) illustrates miR-3682-3p targets PHLDA1, which shows negative correlation demonstrated by dual-luciferase reporter system. To make functional verification of PHLDA1, we upregulate the gene and rescue tests are established to confirm that miR-3682-3p suppresses PHLDA1 to promotion of cell growth. Rescue experiments finish making confirmation of relation of miR-3682-3p and PHLDA1 subsequently. Cirrhotic tissues illustrate strong correlation to higher miR-3682-3p and clinical features make the hint that high-extracellular-matrix-stiffness environment promotes such miRNA. Functional tests on different stiffness provide the proof of underlying mechanism. In conclusion, the overexpression of miR-3682-3p mediates PHLDA1 inhibition could impede apoptosis and elevate proliferation of HCC through high-extracellular-matrix-stiffness environment potentially.

Keywords: MicroRNA-3682-3p, extracellular matrix stiffness, PHLDA1, apoptosis, hepatocellular carcinoma