HBV-encoded miR-2 functions as an oncogene by downregulating TRIM35 but upregulating RAN in liver cancer cellsResearch in context
Lili Yao,
Yadi Zhou,
Zhenhua Sui,
Yanling Zhang,
Yankun Liu,
Hong Xie,
Huijie Gao,
Hongxia Fan,
Yi Zhang,
Min Liu,
Shengping Li,
Hua Tang
Affiliations
Lili Yao
Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
Yadi Zhou
Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
Zhenhua Sui
Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
Yanling Zhang
Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
Yankun Liu
The Cancer Institute, Tangshan People's Hospital, Tangshan 063001, China
Hong Xie
Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
Huijie Gao
Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
Hongxia Fan
Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
Yi Zhang
Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
Min Liu
Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China
Shengping Li
State Key Laboratory of Oncology in Southern China, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China
Hua Tang
Tianjin Life Science Research Center, Tianjin Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, Basic Medical School, Tianjin Medical University, Tianjin 300070, China; Corresponding author at: No. 22 Qi-Xiang-Tai Road, Tianjin 300070, China.
Background: 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. Methods: 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. To evaluate the roles of HBV-miR-2 in liver cancer cells, we determined cell viability and migration/invasion ability by gain-of-function experiment in HBV(−) liver cancer cells (HepG2 and Huh7) and loss-of-function experiments in Huh7 cells stably expressing HBV-miR-2 (Huh7/HBV-miR-2 cells) and HepG2.2.15 cells. Furthermore, to elucidate the mechanism by which HBV-miR-2 work on cell malignancy, we identified and studied the effect of two target genes (TRIM35 and RAN) of HBV-miR-2 in liver cancer cells. Findings: 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. Interpretation: Our findings indicate that an HBV-encoded miRNA, HBV-miR-2, promotes oncogenic activity by downregulating TRIM35 expression and upregulating RAN expression in liver cancer cells, likely providing insight into tumorigenesis in HBV-related liver cancer. Fund: This work was supported in part by the National Natural Science Foundation of China (No: 81830094; 91629302; 31270818) and the Natural Science Foundation of Tianjin (No: 12JCZDJC25100). Keywords: HBV, miRNA, Liver cancer, Proliferation, Invasion
