Hepatitis B Virus-Encoded MicroRNA (HBV-miR-3) Inhibits FIH-1 Expression to Promote Tumor Angiogenesis in HBV-Related Hepatocellular Carcinoma

Han Chen; Dan Cao; Ning Han; Mingming Zhang; Wei Jiang; Xin Wang; Qinmin Zeng; Hong Tang

doi:10.2147/JHC.S436926

Hepatitis B Virus-Encoded MicroRNA (HBV-miR-3) Inhibits FIH-1 Expression to Promote Tumor Angiogenesis in HBV-Related Hepatocellular Carcinoma

J Hepatocell Carcinoma. 2023 Dec 27:10:2337-2353. doi: 10.2147/JHC.S436926. eCollection 2023.

Authors

Han Chen^{1

2}, Dan Cao^{1

2}, Ning Han^{1

2}, Mingming Zhang^{1

2}, Wei Jiang^{1

2}, Xin Wang^{1

2}, Qinmin Zeng^{1

2}, Hong Tang^{1

2}

Affiliations

¹ Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People's Republic of China.
² Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People's Republic of China.

Abstract

Introduction: Hepatocellular carcinoma (HCC) is a solid tumor with a rich blood supply, and anti-angiogenesis has important clinical significance. Hepatitis B Virus-Encoded MicroRNA 3 (HBV-miR-3) has recently been reported to be involved in HCC development. In this study, we aim to elucidate the role of HBV-miR-3 in promoting HBV-related HCC angiogenesis through Factor Inhibiting Hypoxia-inducible factor 1 (FIH-1).

Results: By analyzing HBV-related HCC tissue samples, we found that high expression of HBV-miR-3 was associated with poor overall survival and HBV-miR-3 expression was significantly correlated with VEGFR2 and FIH-1 expressions. In vitro, HBV-miR-3 agomir repressed FIH-1 expression and promoted HIF-1α/VEGFA signaling activation in HepG2 cells, resulting in increased HUVEC lumen formation in HepG2-HUVEC co-culture model. Conversely, HBV-miR-3 antagomir induced FIH-1 expression and inhibited HIF-1α/VEGFA signaling activation in HepG2.2.15 cells, resulting in decreased HUVEC lumen formation in HepG2.2.15-HUVEC co-culture model. The effect of HBV-miR-3 to HCC angiogenesis was also confirmed by a mouse tumor bearing model. We also confirmed that HBV-miR-3 repressed FIH-1 expression via targeting the 3'-UTR of FIH-1 mRNA by luciferase activity assay.

Conclusion: HBV-miR-3 was related to HCC patients' overall survival and it promoted angiogenesis by repressing FIH-1 expression. HBV-miR-3 may be a new marker for predicting prognosis and a novel target for anti-angiogenic treatment of HBV-related HCC.

Keywords: FIH-1; HBV-miR-3; HBV-related HCC; angiogenesis.

Grants and funding

This work was supported by the National Key Research and Development Program of China (NO.2022YFC2304800) and 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD20009).