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Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis.
Cancer Lett. 2017 05 28; 394:22-32.CL

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+Show Affiliations

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.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.Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.National Center for Liver Cancer, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.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.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.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.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.Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.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.Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28216372

Citation

Chen, Shuzhen, et al. "Hepatitis B Virus X Protein Stimulates High Mobility Group Box 1 Secretion and Enhances Hepatocellular Carcinoma Metastasis." Cancer Letters, vol. 394, 2017, pp. 22-32.
Chen S, Dong Z, Yang P, et al. Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis. Cancer Lett. 2017;394:22-32.
Chen, S., Dong, Z., Yang, P., Wang, X., Jin, G., Yu, H., Chen, L., Li, L., Tang, L., Bai, S., Yan, H., Shen, F., Cong, W., Wen, W., & Wang, H. (2017). Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis. Cancer Letters, 394, 22-32. https://doi.org/10.1016/j.canlet.2017.02.011
Chen S, et al. Hepatitis B Virus X Protein Stimulates High Mobility Group Box 1 Secretion and Enhances Hepatocellular Carcinoma Metastasis. Cancer Lett. 2017 05 28;394:22-32. PubMed PMID: 28216372.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis. AU - Chen,Shuzhen, AU - Dong,Zihui, AU - Yang,Pinghua, AU - Wang,Xianming, AU - Jin,Guangzhi, AU - Yu,Han, AU - Chen,Lei, AU - Li,Liang, AU - Tang,Liang, AU - Bai,Shilei, AU - Yan,Hexin, AU - Shen,Feng, AU - Cong,Wenming, AU - Wen,Wen, AU - Wang,Hongyang, Y1 - 2017/02/17/ PY - 2016/11/13/received PY - 2017/01/17/revised PY - 2017/02/10/accepted PY - 2017/2/22/pubmed PY - 2017/8/8/medline PY - 2017/2/21/entrez KW - Calmodulin dependent protein kinase KW - Hepatitis B virus X protein KW - Hepatocellular carcinoma KW - High mobility group box 1 KW - Metastasis SP - 22 EP - 32 JF - Cancer letters JO - Cancer Lett. VL - 394 N2 - : 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. SN - 1872-7980 UR - https://www.unboundmedicine.com/medline/citation/28216372/Hepatitis_B_virus_X_protein_stimulates_high_mobility_group_box_1_secretion_and_enhances_hepatocellular_carcinoma_metastasis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(17)30111-8 DB - PRIME DP - Unbound Medicine ER -