Expression of Yes-associated protein modulates Survivin expression in primary liver malignancies

• Published in: Human pathology Vol. 43; no. 9; pp. 1376 - 1385
• Main Authors: Bai, Haibo, PhD, Gayyed, Mariana F., MD, Lam-Himlin, Dora M., MD, Klein, Alison P., PhD, Nayar, Suresh K, Xu, Yang, MD, PhD, Khan, Mehtab, MS, Argani, Pedram, MD, Pan, Duojia, PhD, Anders, Robert A., MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.2012; Elsevier; Elsevier Limited
• Subjects: Animals; Apoptosis; Biological and medical sciences; Cancer; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Cycle Proteins; Cholangiocarcinoma; Cholangiocarcinoma - genetics; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; Gastroenterology. Liver. Pancreas. Abdomen; Hepatocellular carcinoma; Humans; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Investigative techniques, diagnostic techniques (general aspects); Liver; Liver - metabolism; Liver - pathology; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Transgenic; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Proteins; Rodents; Survivin; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; Yes-associated protein; Yes-associated protein; Hepatocellular carcinoma; Survivin; Cholangiocarcinoma; Digestive system; Liver; Hepatic disease; Malignancy; Malignant tumor; Biliary tract disease; Liver cancer; Anatomic pathology; Apoptosis inhibitory protein; Malignant cholangioma; Primary; Digestive diseases; Cancer
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2011.12.001

Summary 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.