PMID- 27821177 OWN - NLM STAT- MEDLINE DCOM- 20171213 LR - 20201209 IS - 1756-9966 (Electronic) IS - 0392-9078 (Print) IS - 0392-9078 (Linking) VI - 35 IP - 1 DP - 2016 Nov 7 TI - Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-kappaB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells. PG - 172 LID - 172 AB - BACKGROUND: Interleukin-7 receptor (IL-7R) is involved in the abnormal function of solid tumors, but the role and regulatory mechanisms of IL-7R in HBV-related hepatocellular carcinoma (HCC) are still unclear. METHODS: Gene and protein expression levels of IL-7R were examined in hepatoma cells transfected with hepatitis B virus (HBV) plasmids and in hepatoma cells transfected with the multifunctional nonstructural protein X (HBX). The expression of HBX and IL-7R was measured by immunohistochemical analysis in HBV-related HCC tissues. The role of NF-kappaB and Notch1 pathways in HBX-mediated expression of IL-7R in hepatoma cells was examined. Activation of IL-7R downstream of intracellular signaling proteins AKT, JNK, STAT5, and the associated molecules CyclinD1 and matrix metalloproteinase-9 (MMP)-9, was assessed in HBX-positive cells with or without treatment with IL-7R short hairpin RNA (shRNA). Additionally, the role of IL-7R in HBX-mediated proliferation and migration of hepatoma cells was investigated. RESULTS: The expression of IL-7R was increased in hepatoma cells transfected with HBV plasmids; HBX was responsible for the HBV-mediated upregulation of IL-7R. Compared to adjacent tissues, the expression of HBX and IL-7R was increased in HBV-related HCC tissues. Additionally, the relative expression levels of HBX were associated with IL-7R in HBV-related HCC tissues. The activation of NF-kappaB pathways and expression of Notch1 were increased in hepatoma cells transfected with HBX, and inhibition of NF-kappaB and Notch1 pathways significantly decreased HBX-mediated expression of IL-7R. The activation of AKT and JNK and the expression of CyclinD1 and MMP-9 were increased in HBX-positive cells. When cells were treated with IL-7R shRNA, the activation of AKT and JNK, as well as the expression of CyclinD1 and MMP-9, were significantly inhibited. Additionally, IL-7R was responsible for HBX-induced proliferation and migration ability of hepatoma cells. CONCLUSIONS: Our data demonstrate that HBX can upregulate IL-7R via NF-kappaB and Notch1 pathways to facilitate the activation of intracellular pathways and expression of associated molecules, and contribute to proliferation and migration of hepatoma cells. FAU - Kong, Fanyun AU - Kong F AD - Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. FAU - Hu, Wei AU - Hu W AD - Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. AD - Department of Clinical Laboratory, Suqian People's Hospital, Nanjing Drum Tower Hospital Group, Suqian, Jiangsu, 223800, China. FAU - Zhou, Kai AU - Zhou K AD - Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. FAU - Wei, Xiao AU - Wei X AD - Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. FAU - Kou, Yanbo AU - Kou Y AD - Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. FAU - You, Hongjuan AU - You H AD - Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. FAU - Zheng, Kuiyang AU - Zheng K AD - Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. zky02@163.com. FAU - Tang, Renxian AU - Tang R AD - Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. tangrenxian-t@163.com. LA - eng PT - Journal Article DEP - 20161107 PL - England TA - J Exp Clin Cancer Res JT - Journal of experimental & clinical cancer research : CR JID - 8308647 RN - 0 (IL7R protein, human) RN - 0 (Interleukin-7 Receptor alpha Subunit) RN - 0 (NF-kappa B) RN - 0 (NOTCH1 protein, human) RN - 0 (Receptor, Notch1) RN - 0 (Trans-Activators) RN - 0 (Viral Regulatory and Accessory Proteins) RN - 0 (hepatitis B virus X protein) SB - IM MH - Carcinoma, Hepatocellular/immunology/*virology MH - Cell Line, Tumor MH - Cell Movement MH - Cell Proliferation MH - Gene Expression Regulation, Neoplastic MH - Hep G2 Cells MH - Hepatitis B/*immunology MH - Humans MH - Interleukin-7 Receptor alpha Subunit/*metabolism MH - Liver Neoplasms/immunology/*virology MH - NF-kappa B/metabolism MH - Receptor, Notch1/metabolism MH - Signal Transduction MH - Trans-Activators/*immunology MH - Up-Regulation MH - Viral Regulatory and Accessory Proteins PMC - PMC5100324 OTO - NOTNLM OT - Hepatitis B virus X protein OT - Hepatocellular carcinoma OT - Interleukin-7 receptor OT - Migration OT - Proliferation EDAT- 2016/11/09 06:00 MHDA- 2017/12/14 06:00 PMCR- 2016/11/07 CRDT- 2016/11/09 06:00 PHST- 2016/06/19 00:00 [received] PHST- 2016/10/24 00:00 [accepted] PHST- 2016/11/09 06:00 [entrez] PHST- 2016/11/09 06:00 [pubmed] PHST- 2017/12/14 06:00 [medline] PHST- 2016/11/07 00:00 [pmc-release] AID - 10.1186/s13046-016-0448-2 [pii] AID - 448 [pii] AID - 10.1186/s13046-016-0448-2 [doi] PST - epublish SO - J Exp Clin Cancer Res. 2016 Nov 7;35(1):172. doi: 10.1186/s13046-016-0448-2.