title: Dysregulation of the TGFBI gene is involved in the oncogenic activity of the nonsense mutation of hepatitis B virus surface gene sW182*.
abstract: The nonsense mutations of the hepatitis B virus (HBV) surface (S) gene have been reported to have oncogenic potential. We have previously identified several transforming nonsense mutations of the HBV S gene from hepatocarcinoma (HCC) patients. Among them, the sW182* mutant (the stop codon for tryptophan 182) showed the most potent oncogenicity in a mouse xenograft model using stably transfected mouse fibroblast cells. This study is aimed at understanding the molecular mechanisms leading to the oncogenic activity of the sW182* mutant. A gene expression microarray in combination with gene set enrichment analysis (GSEA) revealed differentially expressed gene sets in the sW182* cells, including those related to cell-cycle regulation, deoxyribonucleic acid repair, and genome instability. Of the differentially expressed genes, the transforming growth factor-β-induced (TGFBI) gene was further validated to be dysregulated in the sW182* cells. This dysregulation was accompanied by hypermethylation of the TGFBI promoter. The level of cyclin D1, a negatively regulated TGFBI target, was highly elevated in the sW182* mutant cells, which is consistent with the potent oncogenicity. Furthermore, frequent abnormal mitosis and multinucleation were observed in the mutant cells. Exogenous expression of TGFBI alleviated the oncogenic activity of the sW182* cells. In human HBV-related HCC cancerous tissue, expression of TGFBI was downregulated in 25 of the 55 (45%) patients examined, suggesting that TGFBI dysregulation could occur in HBV-related HCC development in some cases. These results suggest that dysregulation of TGFBI is involved in the oncogenic activity of the sW182* mutant of the hepatitis B virus S gene.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Shih Sheng
authors.initials: SS
authors.lastname: Jiang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan; Department of Pathology, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Huang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Min-Syuan
authors.initials: MS
authors.lastname: Huang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan; Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Yng-Tay
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Hsiang-Ju
authors.initials: HJ
authors.lastname: Jhong
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Il-Chi
authors.initials: IC
authors.lastname: Chang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Jer-Wei
authors.initials: JW
authors.lastname: Chang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Wen-Ling
authors.initials: WL
authors.lastname: Chen
authors.affiliation: Department of Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
authors.forename: Wei-Chen
authors.initials: WC
authors.lastname: Lee
authors.affiliation: Department of Surgery, Chang-Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
authors.forename: Miin-Fu
authors.initials: MF
authors.lastname: Chen
authors.affiliation: Liver Research Center, Chang-Gung Memorial Hospital at Linkou, Taiwan.
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan. Electronic address: imatsuura@nhri.org.tw.
authors.forename: Isao
authors.initials: I
authors.lastname: Matsuura
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000821:virology; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D018389:Codon, Nonsense; D019938:Cyclin D1 / Q000235:genetics; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D015870:Gene Expression; D042822:Genomic Instability; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics*; D000099222:betaIG-H3 Protein
chemical_list: D018389:Codon, Nonsense; D019938:Cyclin D1; D016326:Extracellular Matrix Proteins; D006514:Hepatitis B Surface Antigens; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C530104:CCND1 protein, human
keywords: Cyclin D1; HBV PreS/S gene; HCC; Hepatocarcinogenesis; Nonsense mutation; TGFBI