title: Hepatitis B virus X induces inflammation and cancer in mice liver through dysregulation of cytoskeletal remodeling and lipid metabolism.
abstract: 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.
authors.affiliation: State 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.|Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin, 300309, P.R. China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Xu
authors.affiliation: State 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.
authors.forename: Linghui
authors.initials: L
authors.lastname: Zhai
authors.affiliation: State 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.|Anhui Medical University, Hefei, 230032, P.R. China.
authors.forename: Tailong
authors.initials: T
authors.lastname: Yi
authors.affiliation: State 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.
authors.forename: Huiying
authors.initials: H
authors.lastname: Gao
authors.affiliation: State 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.|Anhui Medical University, Hefei, 230032, P.R. China.
authors.forename: Fengxu
authors.initials: F
authors.lastname: Fan
authors.affiliation: State 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.
authors.forename: Yanchang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Beijing Institute of Bioengineering, Beijing, 100071, P. R. China.
authors.forename: Youliang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State 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.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: State 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.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xing
authors.affiliation: State 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.
authors.forename: Na
authors.initials: N
authors.lastname: Su
authors.affiliation: State 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.
authors.forename: Feilin
authors.initials: F
authors.lastname: Wu
authors.affiliation: State 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Chang
authors.affiliation: The Fifth Hospital of Shijiazhuang City, Shijiazhuang, 050021, P.R. China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Chen
authors.affiliation: The Fifth Hospital of Shijiazhuang City, Shijiazhuang, 050021, P.R. China.
authors.forename: Erhei
authors.initials: E
authors.lastname: Dai
authors.affiliation: Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, and Research Center on Aging and Medicine, Fudan University, Shanghai, 200032, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Beijing Institute of Bioengineering, Beijing, 100071, P. R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: State 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.
authors.forename: Chunping
authors.initials: C
authors.lastname: Cui
authors.affiliation: State 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.|Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and Wuhan University School of Pharmaceutical Sciences, Wuhan, 430072, P. R. China.|Anhui Medical University, Hefei, 230032, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006509:Hepatitis B / Q000235:genetics / Q000378:metabolism / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D007553:Isotope Labeling / Q000379:methods; D050356:Lipid Metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000070780:Perilipin-2 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D020543:Proteome; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein
keywords: ADFP; CDC42; CFL1; HBx; SILAM