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.

Hepatitis B Virus X Protein Stimulates Proliferation, Wound Closure and Inhibits Apoptosis of HuH-7 Cells via CDC42

“…Our previous quantitative proteomic studies of HBx transgenic mice suggested that the CDC42 together with its downstream signaling mediators, such as IQ Motif Containing GTPase Activating Protein 1 (IQGAP1), Septin-1, and Cofilin-1 (Figure 1A), play a vital role in HBx induced carcinogenesis of mouse hepatocytes [12]. Therefore, we firstly ascertained whether HBx could promote the proliferation of HuH-7 cells.…”

“…In addition, the lipid metabolism and CDC42-induced cytoskeleton remodeling pathways were strongly activated by the HBx transgene. However, the specific function of CDC42 in hepatocyte tumorigenicity has not been fully elucidated [12]. …”

Identification of p90 Ribosomal S6 Kinase 2 as a Novel Host Protein in HBx Augmenting HBV Replication by iTRAQ‐Based Quantitative Comparative Proteomics

“…In this study, pathway analysis also revealed that HBx‐related differentially expressed proteins are associated with lipid metabolism. Previous studies indicated that HBx‐induced abnormal lipid metabolism of hepatoma in hepatocarcinogenesis . This indicates that HBx induces abnormal lipid metabolism to meet the bioenergetic demands of extreme cell growth and proliferation.…”

LysargiNase enhances protein identification on the basis of trypsin on formalin‐fixed paraffin‐embedded samples

“…Liquid chromatography/tandem mass spectrometry (LC/MS/MS) experiments were performed as described previously . In brief, each peptide mixture was separated and analyzed by using an ultra‐performance liquid chromatography (nano Acquity UPLC system, Waters, Milford, MA, USA)/MS/MS (LTQ Orbitrap Velos, Thermo Fisher Scientific, San Jose, CA, USA) platform.…”