HBV-induced miR-4461 downregulation correlates with elevated fibrinogen alpha chain expression in hepatocellular carcinoma

BACKGROUND: Hepatitis B virus (HBV) infection remains a leading cause of hepatocellular carcinoma (HCC), yet the molecular mechanisms underlying HBV-mediated hepatocarcinogenesis are not fully understood. This study focused on miR-4461, which is encoded within the intronic region of PCBD2 gene, and investigated its role in HBV-derived HCC. METHODS: miR-4461 expression was examined in HBV-expressing hepatoma cell lines and in HBV-infected primary human hepatocytes. Functional analysis evaluated the effects of miR-4461 overexpression or inhibition on hepatocyte proliferation. Candidate targets were screened, and fibrinogen alpha chain (FGA) was tested for regulation by miR-4461. Circulating miR-4461 and plasma FGA were measured in patients with chronic viral hepatitis, including those with HBV-related HCC; in the HBV-HCC cohort, FGA was also assessed before and after surgical tumor resection. RESULTS: miR-4461 expression was significantly reduced in HBV-expressing hepatoma cells and HBV-infected primary hepatocytes. Overexpression of miR-4461 inhibited hepatocyte proliferation, whereas its inhibition enhanced proliferation, indicating a tumor-suppressive function. FGA was identified as a downstream target; in hepatoma cells, FGA protein levels were regulated by miR-4461. Clinically, circulating miR-4461 levels were significantly lower in HBV-infected individuals, particularly in those with HBV-related HCC. In contrast, plasma FGA protein levels were markedly elevated in HBV-related HCC and decreased significantly after tumor resection. CONCLUSIONS: These findings suggest a novel regulatory axis in HBV-associated HCC involving HBV-induced suppression of miR-4461 and subsequent upregulation of FGA. Both miR-4461 and FGA were associated with disease status, supporting their potential utility as biomarkers or therapeutic targets in HBV-derived HCC.