title: 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.
  
  
  
  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.affiliation: 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.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Zihui
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Pinghua
authors.initials: P
authors.lastname: Yang
authors.affiliation: National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Xianming
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Jin
authors.affiliation: 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.
authors.forename: Han
authors.initials: H
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Shilei
authors.initials: S
authors.lastname: Bai
authors.affiliation: 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.
authors.forename: Hexin
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Shen
authors.affiliation: Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Wenming
authors.initials: W
authors.lastname: Cong
authors.affiliation: 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.
authors.forename: Wen
authors.initials: W
authors.lastname: Wen
authors.affiliation: 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.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D065096:Calcium Chelating Agents / Q000494:pharmacology; D020013:Calcium Signaling; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000556:secondary / Q000628:therapy / Q000821:virology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D015967:Gene Expression Regulation, Viral; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006509:Hepatitis B / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy / Q000821:virology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000517:prevention & control / Q000556:secondary / Q000821:virology; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D019562:Viral Load; D054334:Viral Regulatory and Accessory Proteins; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D065096:Calcium Chelating Agents; D004279:DNA, Viral; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D047428:Protein Kinase Inhibitors; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C517683:CAMK4 protein, human; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4
keywords: Calmodulin dependent protein kinase; Hepatitis B virus X protein; Hepatocellular carcinoma; High mobility group box 1; Metastasis