Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells.
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.



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-κB 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.



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-κB pathways and expression of Notch1 were increased in hepatoma cells transfected with HBX, and inhibition of NF-κB 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.



Our data demonstrate that HBX can upregulate IL-7R via NF-κB and Notch1 pathways to facilitate the activation of intracellular pathways and expression of associated molecules, and contribute to proliferation and migration of hepatoma cells.
Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
Fanyun
F
Kong
Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.|Department of Clinical Laboratory, Suqian People's Hospital, Nanjing Drum Tower Hospital Group, Suqian, Jiangsu, 223800, China.
Wei
W
Hu
Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
Kai
K
Zhou
Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
Xiao
X
Wei
Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
Yanbo
Y
Kou
Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
Hongjuan
H
You
Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. zky02@163.com.
Kuiyang
K
Zheng
Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. tangrenxian-t@163.com.
Renxian
R
Tang
D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000821:virology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000276:immunology*; D006801:Humans; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism*; D008113:Liver Neoplasms / Q000276:immunology / Q000821:virology*; D016328:NF-kappa B / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000276:immunology*; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins
C000620371:IL7R protein, human; D053699:Interleukin-7 Receptor alpha Subunit; D016328:NF-kappa B; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein
Hepatitis B virus X protein; Hepatocellular carcinoma; Interleukin-7 receptor; Migration; Proliferation