Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis.

Abstract

Hepatitis B virus X protein (HBx) plays an important role in the progression of hepatocellular carcinoma. Here we reported that overexpression of HBx in hepatocellular carcinoma (HCC) cells could induce the secretion of high-mobility group box 1 (HMGB1) to promote invasion and metastasis of HCC in an autocrine/paracrine manner. HBx triggered an increase of cytoplasmic calcium and activated CAMKK/CAMKIV pathway, leading to subsequent translocation and release of HMGB1. HMGB1 neutralizing antibody, as well as calcium chelator or inhibitors of CAMKK/CAMKIV, could remarkably reduce invasion and metastasis of HCC cells in vitro and in a murine HCC metastasis model in vivo. Furthermore, the level of HMGB1 in patient serum and tumor tissues was positively correlated with HBV DNA load. We demonstrate an inverse relationship between HMGB1 in tumor cytoplasm and overall prognosis of HCC patients.

CONCLUSION:

HBx promotes the progression of HCC through translocation and secretion of HMGB1 from tumor cells via calcium dependent cascades. These data indicates that HMGB1 could serve as a novel prognostic biomarker and potential therapeutic target for HBV-related HCC.

• Authors: Shuzhen Chen, Zihui Dong, Pinghua Yang, Xianming Wang, Guangzhi Jin, Han Yu, Lei Chen, Liang Li, Liang Tang, Shilei Bai, Hexin Yan, Feng Shen, Wenming Cong, Wen Wen, Hongyang Wang
• Journal: Cancer letters (Cancer Lett) Vol. 394 Pg. 22-32 (05 28 2017) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 28216372 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Antibodies
• Antineoplastic Agents
• Calcium Chelating Agents
• DNA, Viral
• HMGB1 Protein
• HMGB1 protein, human
• Protein Kinase Inhibitors
• Trans-Activators
• Viral Regulatory and Accessory Proteins
• hepatitis B virus X protein
• CAMK4 protein, human
• Calcium-Calmodulin-Dependent Protein Kinase Kinase
• Calcium-Calmodulin-Dependent Protein Kinase Type 4

Topics

• Animals
• Antibodies (pharmacology)
• Antineoplastic Agents (therapeutic use)
• Calcium Chelating Agents (pharmacology)
• Calcium Signaling
• Calcium-Calmodulin-Dependent Protein Kinase Kinase (antagonists & inhibitors, metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 4 (antagonists & inhibitors, metabolism)
• Carcinoma, Hepatocellular (metabolism, secondary, therapy, virology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• DNA, Viral (genetics)
• Female
• Gene Expression Regulation, Viral
• HMGB1 Protein (antagonists & inhibitors, metabolism)
• Hepatitis B (complications, genetics, metabolism, virology)
• Hepatitis B virus (genetics, metabolism)
• Host-Pathogen Interactions
• Humans
• Liver Neoplasms (metabolism, pathology, therapy, virology)
• Lung Neoplasms (metabolism, prevention & control, secondary, virology)
• Male
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Prognosis
• Proportional Hazards Models
• Protein Kinase Inhibitors (pharmacology)
• Time Factors
• Trans-Activators (genetics, metabolism)
• Transfection
• Viral Load
• Viral Regulatory and Accessory Proteins
• Xenograft Model Antitumor Assays