title: Dual oncogenic and tumor suppressor roles of the promyelocytic leukemia gene in hepatocarcinogenesis associated with hepatitis B virus surface antigen.
abstract: Proteasome-mediated degradation of promyelocytic leukemia tumor suppressor (PML) is upregulated in many viral infections and cancers. We previously showed that PML knockdown promotes early-onset hepatocellular carcinoma (HCC) in hepatitis B virus surface antigen (HBsAg)-transgenic mice. Here we report the effects of PML restoration on late-onset HBsAg-induced HCC. We compared protein expression patterns, genetic mutations and the effects of pharmacologically targeting PML in wild-type, PML-/-, PML+/+HBsAgtg/o and PML-/-HBsAgtg/o mice. PML-/- mice exhibited somatic mutations in DNA repair genes and developed severe steatosis and proliferative disorders, but not HCC. PML-/-HBsAgtg/o mice exhibited early mutations in cancer driver genes and developed hyperplasia, fatty livers and indolent adipose-like HCC. In PML+/+HBsAg-transgenic mice, HBsAg expression declined over time, and HBsAg-associated PML suppression was concomitantly relieved. Nevertheless, these mice accumulated mutations in genes contributing to oxidative stress pathways and developed aggressive late-onset angiogenic trabecular HCC. PML inhibition using non-toxic doses of arsenic trioxide selectively killed long-term HBsAg-affected liver cells in PML+/+HBsAgtg/o mice with falling HBsAg and rising PML levels, but not normal liver cells or early-onset HCC cells in PML-/-HBsAgtg/0 mice. These findings suggest dual roles for PML as a tumor-suppressor lost in early-onset HBsAg-induced hepatocarcinogenesis and as an oncogenic promoter in late-onset HBsAg-related HCC progression.
authors.affiliation: Department of Radiation Oncology, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan.
authors.forename: Yih-Lin
authors.initials: YL
authors.lastname: Chung
authors.affiliation: Department of Pathology and Laboratory Medicine, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Wu
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006514:Hepatitis B Surface Antigens / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009857:Oncogenes / Q000502:physiology; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D006514:Hepatitis B Surface Antigens; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein
keywords: PML; hepatitis B virus; hepatocarcinogenesis; oncogene; tumor suppressor