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

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

doi:10.1016/j.canlet.2017.02.011

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

Cancer Lett. 2017 May 28:394:22-32. doi: 10.1016/j.canlet.2017.02.011. Epub 2017 Feb 17.

Authors

Shuzhen Chen¹, Zihui Dong¹, Pinghua Yang², Xianming Wang³, Guangzhi Jin⁴, Han Yu¹, Lei Chen¹, Liang Li¹, Liang Tang¹, Shilei Bai², Hexin Yan¹, Feng Shen², Wenming Cong⁴, Wen Wen⁵, Hongyang Wang⁶

Affiliations

¹ National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
² Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
³ National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
⁴ Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
⁵ National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: wenwen_smmu@163.com.
⁶ National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China; Ministry of Education (MOE) Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Second Military Medical University, Shanghai, China. Electronic address: hywangk@vip.sina.com.

PMID: 28216372
DOI: 10.1016/j.canlet.2017.02.011

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.

Keywords: Calmodulin dependent protein kinase; Hepatitis B virus X protein; Hepatocellular carcinoma; High mobility group box 1; Metastasis.

MeSH terms

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

Substances

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