HBx mutant-regulated RPL13AP25 mediates suboptimal virological response to entecavir and HCC progression

Area of Science:

• Hepatology
• Virology
• Oncology

Background:

• Effective antiviral agents for chronic hepatitis B (CHB) exist, but suboptimal responses occur in some patients.
• The role of long non-coding RNAs (lncRNAs) in mediating suboptimal CHB responses is not fully understood.

Purpose of the Study:

• To investigate the contribution of lncRNAs in suboptimal responses in CHB patients.
• To explore the link between suboptimal response, HBx mutations, and hepatocellular carcinoma (HCC) development.

Main Methods:

• Cox regression models analyzed clinical factors associated with suboptimal response.
• Hepatitis B virus X (HBx) gene sequencing was performed on entecavir-treated patients who developed HCC.
• Functional assays (Transwell, MTT, xenograft) and RNA-seq were employed.

Main Results:

• Suboptimal response independently predicted HCC development.
• HBx mutations were identified in 5/6 HCC patients with suboptimal response.
• The HBx-H94Y/K130M mutant increased cccDNA accumulation and cell migration, upregulating RPL13AP25, a marker associated with poor survival and HCC progression.

Conclusions:

• The HBx-H94Y/K130M mutant, selected during suboptimal response, promotes cccDNA accumulation via RPL13AP25 upregulation.
• This mechanism contributes to hepatocellular carcinoma progression in CHB patients.