Molecular pathways affected by HBx protein and their targeting for therapy of Hepatocellular carcinoma

Abstract

Hepatitis B virus (HBV) infection can cause several types of liver disease including acute hepatitis, chronic hepatitis, and liver cirrhosis. It is also considered a significant risk factor for Hepatocellular carcinoma (HCC) due to HBV integration, continuous expression of the Hepatitis B X protein (HBx), and epigenetic dysregulation of tumor suppressor genes. This study focuses on the involvement of HBx in the initiation and progression of HCC, through activation of transcription factors, production of reactive oxygen species (ROSs), and modulation of the expression of cell cycle regulatory molecules such as p27, p21, p53, cyclin D1, PARP, and Bax. In addition, it analyzes how HBx has been linked to the development of liver inflammation and HCC through the modulation of multiple intracellular signaling pathways such as NF-κB, P13K- Akt, p38 MAPK, MyD88 and IRAK-1. Finally, this work focuses on how HBx influences the expression of numerous microRNAs, such as miR-221, promoting cell proliferation by suppression of ERα, thus acting as a tumor promoter. Therefore, miR-221 overexpression could potentially serve as a novel biomarker for HBV-related HCC and a potential target for a miRNA- based molecular therapeutic strategy. HBx also upregulates the expression of miR-137 by restricting its methylation. Overexpression of miR-137 however was shown to inhibit HCC cell proliferation through Notch1 targeting. Therapeutic strategies targeting miR-137 could therefore prove beneficial. Overall, this study analyzes significant mechanisms underlying HBx-induced HCC and focuses on how they may be targeted for therapy.