HBV-Encoded miR-2 Functions as an Oncogene by Downregulating TRIM35 But Upregulating RAN in Liver Cancer Cells

Hepatitis B virus (HBV) infection has been well established as a high-risk factor for the carcinogenesis of hepatocellular carcinoma (HCC). Cellular microRNA (miRNA) is involved in tumorigenesis by accelerating the malignant phenotype in HCC. However, whether HBV can encode miRNAs that contribute to HCC is not entirely clear. In this study, an miRNA encoded by HBV (HBV-miR-2) was identified by Solexa sequencing in HBV-positive HCC specimens and further verified in serum samples from HCC patients with HBV infection and in HBV-positive HCC cell lines. We revealed that HBV-miR-2 promoted HCC cell growth ability by suppressing apoptosis and promoting migration and invasion by enhancing the epithelial-mesenchymal transition (EMT), functioning as an oncogene in the development of HBV-related HCC. Furthermore, we demonstrated that HBV-miR-2 suppresses the expression of TRIM35 but enhances RAN expression by targeting their 3'-untranslated regions (3'UTR) and that the ectopic expression of TRIM35 or knockdown of RAN counteracted the malignant phenotypes induced by HBV-miR-2. Funding Statement: This work was supported in part by the National Natural Science Foundation of China (No: 81830094; 91629302; 81572790; 31270818) and the Natural Science Foundation of Tianjin (No: 12JCZDJC25100). Declaration of Interests: All authors declare that there are no potential conflicts of interest. Ethics Approval Statement: The study was approved by the ethics committee of Tianjin Medical University.