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Hepatitis B Virus X Protein Induces RHAMM-Dependent Motility in Hepatocellular Carcinoma Cells via PI3K-Akt-Oct-1
Yu-Chin Liu1, Li-Feng Lu1, Chia-Jung Li1
1Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.
Molecular Cancer Research : MCR
|December 4, 2019
Summary
Hepatitis B virus protein X (HBx) upregulates RHAMM in liver cancer cells by activating the PI3K/Akt/Oct-1 pathway and inhibiting C/EBPβ. This promotes hepatocellular carcinoma (HCC) cell migration and metastasis, indicating RHAMM as a therapeutic target.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Chronic hepatitis B virus (HBV) infection is a primary risk factor for hepatocellular carcinoma (HCC).
- HBV protein X (HBx) is implicated in HCC development, and the receptor for hyaluronan-mediated motility (RHAMM) is a putative oncogene overexpressed in HCC.
- The mechanisms of RHAMM upregulation and its role in tumorigenesis are not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which HBx upregulates RHAMM expression in HCC cells.
- To investigate the role of RHAMM in HBx-induced HCC cell migration, invasion, and metastasis.
- To explore the prognostic significance of RHAMM in HCC patients.
Main Methods:
- Ectopic expression of HBx in HCC cells.
- Analysis of the PI3K/Akt/Oct-1 pathway and C/EBPβ binding to the RHAMM promoter.
- RHAMM knockdown experiments in vitro.
- Tumorigenesis and metastasis studies in mice.
- Analysis of HCC patient gene expression datasets.
Main Results:
- HBx activates the PI3K/Akt/Oct-1 pathway, leading to RHAMM upregulation in HCC cells.
- HBx causes C/EBPβ to dissociate from the RHAMM promoter, inducing RHAMM expression.
- RHAMM knockdown inhibits HBx-induced cell migration and invasion in vitro.
- HBx promotes HCC cell colonization and metastasis in mice via RHAMM upregulation.
- Elevated RHAMM mRNA levels correlate with poor prognosis in HCC patients.
Conclusions:
- HBx-induced RHAMM upregulation is mediated by the PI3K/Akt/Oct-1 pathway and C/EBPβ inhibition.
- RHAMM plays a critical role in HBx-driven HCC cell migration, invasion, and metastasis.
- RHAMM represents a potential therapeutic target for HBV-positive HCC, particularly for managing metastasis.
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