title: Expression of Yes-associated protein modulates Survivin expression in primary liver malignancies.
abstract: Hepatocellular carcinoma and intrahepatic cholangiocarcinoma account for 95% of primary liver cancer. For each of these malignancies, the outcome is dismal; incidence is rapidly increasing, and mechanistic understanding is limited. We observed abnormal proliferation of both biliary epithelium and hepatocytes in mice after genetic manipulation of Yes-associated protein, a transcription coactivator. Here, we comprehensively documented Yes-associated protein expression in the human liver and primary liver cancers. We showed that nuclear Yes-associated protein expression is significantly increased in human intrahepatic cholangiocarcinoma and hepatocellular carcinoma. We found that increased Yes-associated protein levels in hepatocellular carcinoma are due to multiple mechanisms including gene amplification and transcriptional and posttranscriptional regulation. Survivin, a member of the inhibitors-of-apoptosis protein family, has been reported as an independent prognostic factor for poor survival in both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. We found that nuclear Yes-associated protein expression correlates significantly with nuclear Survivin expression for both intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Furthermore, using mice engineered to conditionally overexpress Yes-associated protein in the liver, we found that Survivin messenger RNA expression depends upon Yes-associated protein levels. Our findings suggested that Yes-associated protein contributes to primary liver tumorigenesis and likely mediates its oncogenic effects through modulating Survivin expression.
authors.affiliation: Department of Pathology, Howard Hughes Medical Institute Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Bai
authors.forename: Mariana F
authors.initials: MF
authors.lastname: Gayyed
authors.forename: Dora M
authors.initials: DM
authors.lastname: Lam-Himlin
authors.forename: Alison P
authors.initials: AP
authors.lastname: Klein
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Nayar
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Mehtab
authors.initials: M
authors.lastname: Khan
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Duojia
authors.initials: D
authors.lastname: Pan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C107489:BIRC5 protein, human; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; D009687:Nuclear Proteins; D000077022:Survivin; D014157:Transcription Factors; C456659:YY1AP1 protein, human