期刊
HUMAN PATHOLOGY
卷 43, 期 9, 页码 1376-1385出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1016/j.humpath.2011.12.001
关键词
Yes-associated protein; Survivin; Hepatocellular carcinoma; Cholangiocarcinoma
类别
资金
- National Institute of Health (Bethesda, MD) [R01DK080736, R01DK081417]
- Michael Rolfe Foundation for Pancreatic Cancer Research (Chicago, IL)
- Biliary Cancer Research Fund (Baltimore, MD)
- National Natural Science Foundation of China (Beijing, China) [81030038, 81071661]
- Shanghai Rising-Star Follow-up Program Funds (Shanghai, China) [10QH1400500]
- National Key Sci-Tech Special Project of Infectious Diseases [2008ZX10002-022]
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. (C) 2012 Elsevier Inc. All rights reserved.
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