J Cancer 2018; 9(15):2693-2701. doi:10.7150/jca.25569

Research Paper

The tumor suppressive miR-302c-3p inhibits migration and invasion of hepatocellular carcinoma cells by targeting TRAF4

Liu Yang1,#, Yang Guo2,#, Xin Liu3,#, Tongtong Wang4, Xiangmin Tong1, Kefeng Lei5, Jiahui Wang6, Dongsheng Huang1,✉, Qiuran Xu1,✉

1. Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China
2. Bengbu Medical College, Bengbu, Anhui 233030, China
3. Department of Neurosurgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China
4. ZheJiang Chinese Medical University, Hangzhou, Zhejiang 310014, China
5. Department of Gynecology, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China
6. School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250000, China
#Contributed equally

Abstract

MicroRNAs (miRNAs) have been recognized as key regulators of tumorigenesis and progression. Serum miR-302c-3p expression is prominently deregulated in HCV-related hepatocellular carcinoma (HCC). However, the expression of miR-302c-3p and its functional role in HBV-related HCC are rarely investigated. In this study, we found that the expression levels of miR-302c-3p were prominently down-regulated in HCC tissues compared to matched tumor-adjacent tissues. Moreover, miR-302c-3p under-expression was detected in HCC cell lines compared to a normal hepatic cell line LO2. Low miR-302c-3p expression was positively correlated with multiple tumor nodes, venous infiltration and advanced TNM tumor stage of HCC patients. Notably, our follow up data and TCGA data demonstrated that low miR-302c-3p expression predicted a poor survival of HCC patients. Functionally, miR-302c-3p overexpression inhibited migration and invasion of MHCC97H cells in vitro. Additionally, miR-302c-3p knockdown showed an opposite effect on these metastatic behaviors of HepG2 cells. MiR-302c-3p negatively regulated tumor necrosis factor receptor associated factor 4 (TRAF4) abundance by directly targeting 3'-UTR of TRAF4 mRNA. The expression of TRAF4 was up-regulated in HCC tissues. The level of TRAF4 mRNA was inversely correlated with miR-302c-3p expression in HCC specimens. Mechanistically, miR-302c-3p restrained AKT-mediated epithelial-mesenchymal transition (EMT) in HCC cells. Importantly, TRAF4 restoration reversed the inhibitory effect of miR-302c-3p on AKT-induced EMT and HCC cell metastasis. MK2206, an AKT inhibitor, inhibited miR-302c-3p knockdown-induced EMT in HepG2 cells. In summary, these results indicate that miR-302c-3p exhibits a tumor suppressive role in HCC by targeting TRAF4. Inhibition of miR-302c-3p/TRAF4 axis may serve as a therapeutic target for HCC.

Keywords: miR-302c-3p, TRAF4, hepatocellular carcionoma, EMT, metastasis

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How to cite this article:
Yang L, Guo Y, Liu X, Wang T, Tong X, Lei K, Wang J, Huang D, Xu Q. The tumor suppressive miR-302c-3p inhibits migration and invasion of hepatocellular carcinoma cells by targeting TRAF4. J Cancer 2018; 9(15):2693-2701. doi:10.7150/jca.25569. Available from http://www.jcancer.org/v09p2693.htm