Hepatitis B virus X protein (HBx)-induced abnormalities of nucleic acid metabolism revealed by 1H-NMR-based metabonomics

Abstract

Hepatitis B virus X protein (HBx) plays an important role in HBV-related hepatocarcinogenesis; however, mechanisms underlying HBx-mediated carcinogenesis remain unclear. In this study, an NMR-based metabolomics approach was applied to systematically investigate the effects of HBx on cell metabolism. EdU incorporation assay was conducted to examine the effects of HBx on DNA synthesis, an important feature of nucleic acid metabolism. The results revealed that HBx disrupted metabolism of glucose, lipids, and amino acids, especially nucleic acids. To understand the potential mechanism of HBx-induced abnormalities of nucleic acid metabolism, gene expression profiles of HepG2 cells expressing HBx were investigated. The results showed that 29 genes involved in DNA damage and DNA repair were differentially expressed in HBx-expressing HepG2 cells. HBx-induced DNA damage was further demonstrated by karyotyping, comet assay, Western blotting, immunofluorescence and immunohistochemistry analyses. Many studies have previously reported that DNA damage can induce abnormalities of nucleic acid metabolism. Thus, our results implied that HBx initially induces DNA damage, and then disrupts nucleic acid metabolism, which in turn blocks DNA repair and induces the occurrence of hepatocellular carcinoma (HCC). These findings further contribute to our understanding of the occurrence of HCC.

Multi-omics analyses reveal metabolic alterations regulated by hepatitis B virus core protein in hepatocellular carcinoma cells

“…3D). By contrast, the HBx and HBV co-down-regulated metabolites were related to purine and pyrimidine metabolism, which is also consistent with the documented HBx function24.…”

“…In this study, we found that HBc promoted the expression of metabolic enzymes and the secretion of metabolites in HCC cells. Surprisingly, our results argue that HBc contributes to HBV-related metabolic dysregulation through the modulation of glycolysis and amino acid metabolism, which is significantly different from the metabolic changes in nucleic acid metabolism induced by HBx2324. Meanwhile, a recent study showed that the majority of amino acids (glycine, phenylalanine, glutamic acid, asparagine and tyrosine) were considerably up-regulated in HBV patients, compared with healthy subjects29.…”

“…To validate that HBc may contribute to HBV-related metabolism, we reanalysed and compared recently published metabolomics researches involving HBV23 and HBx24 transfection models. Those studies mentioned above used the same control HepG2 cells as this study and compared them with either HBV-infected HepG2 cells or HepG2 cells transfected with the full-length HBx gene, respectively.…”

“…The metabolomics datasets were collected from our study and published papers2324. The metabolites jointly identified by these studies were selected and analysed here.…”

BNIP3L-Dependent Mitophagy Promotes HBx-Induced Cancer Stemness of Hepatocellular Carcinoma Cells via Glycolysis Metabolism Reprogramming

“…HBx expression also upregulate the transcriptional activity of the sterol regulatory element binding protein-1a (SREBP-1a) [26]. Using nuclear magnetic resonance-based metabolomics methods, it was found that HBx initially induced cellular DNA damage, then disrupted cellular nucleic acid metabolism and prevented DNA repair, inducing HCC [27]. However, there was yet a limited understanding whether HBx can remodel glucose metabolism and what functions and mechanism by which remodeling of glucose metabolism involves in promoting the stemness of HBx-expressing HCC cells.…”