title: Promyelocytic leukaemia protein links DNA damage response and repair to hepatitis B virus-related hepatocarcinogenesis.
abstract: DNA damage response and repair pathways are important barriers to carcinogenesis. Here, we show that promyelocytic leukaemia (PML, also known as TRIM19), involved in sensing DNA damage and executing homologous recombination repair, is down-regulated in non-tumour liver cells surrounding hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). No PML mutation or deletion was found in HBV-infected liver or HCC cells. Immunohistochemical analysis of liver biopsies from patients with breast or liver cancer and HBV reactivation after chemotherapy revealed PML up-regulation and HBV exacerbation in normal liver tissue in response to DNA damage (functional PML), PML down-regulation in HCC peritumour cells associated with high HBsAg accumulation and low HBV replication activity (suppressive PML), and heterogeneous nuclear PML expression in HCC cells that lost HBV DNA and HBsAg and were non-reactive to DNA damage (dysregulated PML). Loss of PML in HBsAg-transgenic mice promoted chromosome breaks in liver cells and accelerated the accumulation of body and liver fat and the development of a liver steatosis-dysplasia-adenoma-carcinoma sequence in an inflammation-independent and male-predominant manner, compared to PML knock-out or HBsAg-transgenic mice during the same time period. These results indicate that PML deficiency facilitates genomic instability and promotes HBsAg-related hepatocarcinogenesis, which also involves androgen and lipid metabolism. These findings uncover a novel PML link between HBV-related tumourigenesis, DNA repair, and metabolism.
authors.affiliation: Department of Radiation Oncology, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, 112, Taiwan. ylchung@kfsyscc.org
authors.forename: Yih-Lin
authors.initials: YL
authors.lastname: Chung
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Wu
mesh_terms: D050154:Adiposity; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002472:Cell Transformation, Viral; D004249:DNA Damage; D004260:DNA Repair; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000627:therapeutic use; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D005260:Female; D042822:Genomic Instability; D006509:Hepatitis B / Q000150:complications* / Q000175:diagnosis / Q000235:genetics; D006514:Hepatitis B Surface Antigens / Q000097:blood / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D012737:Sex Factors; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014775:Virus Activation; D014779:Virus Replication
chemical_list: D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D006514:Hepatitis B Surface Antigens; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D004052:Diethylnitrosamine; D004317:Doxorubicin
keywords: DNA damage response and repair; hepatitis B virus; hepatitis B virus surface antigen; hepatocellular carcinoma; promyelocytic leukaemia protein