Hepatitis B virus X induces inflammation and cancer in mice liver through dysregulation of cytoskeletal remodeling and lipid metabolism
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Zhongwei Xu1,7, Linghui Zhai1, Tailong Yi1,4, Huiying Gao1, Fengxu Fan1,4, Yanchang Li1, Youliang Wang2, Ning Li1, Xiaohua Xing1, Na Su1, Feilin Wu1, Lei Chang1, Xiuli Chen6, Erhei Dai6, Chao Zhao5, Xiao Yang2, Chunping Cui1, Ping Xu1,3,4
1State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
2Beijing Institute of Bioengineering, Beijing, 100071, P. R. China
3Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and Wuhan University School of Pharmaceutical Sciences, Wuhan, 430072, P. R. China
4Anhui Medical University, Hefei, 230032, China
5Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, and Research Center on Aging and Medicine, Fudan University, Shanghai, 200032, China
6The Fifth Hospital of Shijiazhuang City, Shijiazhuang, 050021, China
7Central Laboratory, Logistics University of Chinese People’s Armed Police Force, Tianjin, 300309, China
Ping Xu, email: firstname.lastname@example.org
Keywords: HBx, SILAM, CDC42, CFL1, ADFP
Received: March 10, 2016 Accepted: September 13, 2016 Published: September 30, 2016
Hepatitis B virus X protein (HBx) participates in the occurrence and development processes of hepatocellular carcinoma (HCC) as a multifunctional regulation factor. However, the underlying molecular mechanism remains obscure. Here, we describe the use of p21HBx/+ mouse and SILAM (Stable Isotope Labeling in Mammals) strategy to define the pathological mechanisms for the occurrence and development of HBx induced liver cancer. We systematically compared a series of proteome samples from regular mice, 12- and 24-month old p21HBx/+ mice representing the inflammation and HCC stages of liver disease respectively and their nontransgenic wild-type (WT) littermates. Totally we identified 22 and 97 differentially expressed proteins out of a total of 2473 quantified proteins. Bioinformatics analysis suggested that the lipid metabolism and CDC42-induced cytoskeleton remodeling pathways were strongly activated by the HBx transgene. Interestingly, the protein-protein interaction MS study revealed that HBx directly interacted with multiple proteins in these two pathways. The same effect of up-regulation of cytoskeleton and lipid metabolism related proteins, including CDC42, CFL1, PPARγ and ADFP, was also observed in the Huh-7 cells transfected with HBx. More importantly, CFL1 and ADFP were specifically accumulated in HBV-associated HCC (HBV-HCC) patient samples, and their expression levels were positively correlated with the severity of HBV-related liver disease. These results provide evidence that HBx induces the dysregulation of cytoskeleton remodeling and lipid metabolism and leads to the occurrence and development of liver cancer. The CFL1 and ADFP might be served as potential biomarkers for prognosis and diagnosis of HBV-HCC.
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