Alpha-1B Glycoprotein Is a Novel Hepatocyte-Derived Host Factor Associated with In Vitro Inhibition of HBV Replication and Hepatocellular Carcinoma Progression

TL;DR

Alpha-1B glycoprotein may help fight hepatitis B virus and liver cancer by reducing viral replication and tumor growth in lab models.

Contribution

Alpha-1B glycoprotein is identified as a novel host factor with antiviral and antitumor effects in HBV-related liver cancer.

Findings

Reduced alpha-1B glycoprotein expression is linked to aggressive tumor features and poor prognosis in HBV-associated liver cancer.

Overexpression of alpha-1B glycoprotein inhibits HBV replication and liver cancer cell growth and migration.

Alpha-1B glycoprotein activates antiviral genes and suppresses pathways like FGFR1 and matrix metalloproteinase in liver cancer cells.

Abstract

Hepatitis B virus infection is a leading cause of liver cancer worldwide, yet the host factors involved in this process remain unclear. In our previous study, alpha-1B glycoprotein emerged as a candidate host factor linked to hepatitis B virus infection. As a result, in the present study, we further investigated its role in hepatitis B virus-associated liver cancer. Using liver cancer cell models transfected with hepatitis B virus and patient tissue data, we observed that reduced expression of this protein was associated with more aggressive tumor features and poorer prognosis. Increasing its expression decreased viral markers and inhibited the growth and migration of liver cancer cells. These findings suggest that alpha-1B glycoprotein may exert both antiviral and antitumor effects and could be a potential therapeutic target.

Background: Chronic hepatitis B virus (HBV) infection is a major risk factor of hepatocellular carcinoma (HCC), and hepatocyte-derived host factors play important roles in HBV-associated tumor progression. Alpha-1B glycoprotein (A1BG) is a plasma glycoprotein reported to be dysregulated in multiple cancers. In this study, we investigated the functional role of A1BG in HBV-associated HCC progression. Methods: Both the HepG2 and HBV-transfected HepG2 cell lines were used to examine the biological effects of A1BG. A1BG expression was modulated using siRNA and a plasmid vector. A series of functional assays were conducted to assess cell proliferation, apoptosis, stemness, migration, and invasion. RNA microarray analysis and gene set enrichment analysis (GSEA) were performed to identify A1BG-regulated pathways. Results: Functionally, A1BG overexpression suppressed cell proliferation, stemness, migration, invasion, and HBV products while promoting apoptosis in both HepG2 and HBV-transfected HepG2 cells. In contrast, opposite effects were shown in the event of A1BG knockdown. Moreover, A1BG expression was reduced in HBV-associated HCC tissues and correlated with advanced pathological stage and poor prognosis. RNA microarray analysis and GSEA revealed the activation of anti-HBV-related genes and suppression of FGFR1 signaling and the matrix metalloproteinase pathway in A1BG-overexpressing cells. Conclusions: This study provides evidence that A1BG may be a novel host factor associated with the in vitro suppression of HBV replication and HCC progression by modulating pathways related to enhanced antiviral effects, reduced proliferative capacity and stemness, and suppression of EMT. These findings suggest that A1BG is a potential therapeutic target in HBV-related HCC.

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