title: The potential contributions of a Y-located protooncogene and its X homologue in sexual dimorphisms in hepatocellular carcinoma.
abstract: There is a significant sex disparity favoring males among hepatocellular carcinoma (HCC) patients. Although various risk factors have been identified, the exact etiology of such sexual dimorphism(s) in HCC is uncertain. Previous studies showed that overexpression of the Y-located protooncogene, testis-specific protein Y encoded (TSPY), promotes cell proliferation and oncogenesis whereas its X-located homologue, TSPYhomologue X (TSPX), retards cell cycle and oncogenic progression. Furthermore, TSPX promotes proteasomal degradation of hepatitis B virus-encoded X oncoprotein and hence could serve as a tumor suppressor in virus-associated HCC. Using immunohistochemistry and reverse-transcription polymerase chain reaction analysis, we had examined the expression of TSPY and TSPX with reference to other established biomarkers in HCC and related liver cancers. Our results demonstrated that 55 (19.2%) of 287 male cases were TSPY positive in immunohistochemistry of tissue arrays, and 15 (46.9%) of 32 male cases were TSPY positive in reverse-transcription polymerase chain reaction analysis of clinical samples. TSPY expression was closely associated with the expression of HCC biomarkers, such as glypican 3. In contrast, TSPX expression was down-regulated in 54.5% of total tumor/nontumorous paired samples (18/33) and negatively associated with those of TSPY, glypican 3, and forkhead box M1 (FOXM1) and was positively associated with that of a tumor suppressor, insulin-like growth factor binding protein 3. The present findings support the hypothesis that the oncogenic events leading to an ectopic activation of the Y-located protooncogene TSPY and/or inactivating mutation/epigenetic silencing of the X-located tumor suppressor gene TSPX could collectively contribute to the sexual dimorphism(s) in HCC and related liver cancers in male-biased manners.
authors.affiliation: Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA, 94121, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94121, USA.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kido
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam Rd, Hong Kong, China.
authors.forename: Regina Cheuk-Lam
authors.initials: RC
authors.lastname: Lo
authors.affiliation: Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA, 94121, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94121, USA.
authors.forename: Yunmin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam Rd, Hong Kong, China.
authors.forename: Joyce
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pathology, Veterans Affairs Medical Center, San Francisco, CA, 94121, USA.
authors.forename: Z Laura
authors.initials: ZL
authors.lastname: Tabatabai
authors.affiliation: Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam Rd, Hong Kong, China.
authors.forename: Irene Oi-lin
authors.initials: IO
authors.lastname: Ng
authors.affiliation: Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA, 94121, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94121, USA. Electronic address: chris.lau@ucsf.edu.
authors.forename: Yun-Fai Chris
authors.initials: YF
authors.lastname: Lau
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053673:Glypicans / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms; D017422:Sequence Analysis, DNA; D012737:Sex Factors; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C105937:GPC3 protein, human; D053673:Glypicans; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D009687:Nuclear Proteins; D020033:Protein Isoforms; C497749:TSPY1 protein, human; C432963:TSPYL2 protein, human
keywords: Gonadoblastoma gene; Hepatocellular carcinoma; Sex chromosomes; Sexual dimorphism; TSPX; TSPY