제1저자 김영주(병리학교실, 의과학과 졸, 현 KIST)
교신저자 박영년(병리학교실, BK21)
Int J Cancer. 2018 Jul 10. doi: 10.1002/ijc.31731. [Epub ahead of print]
Suppression of PROX1-mediated TERT expression in hepatitis B viral hepatocellular carcinoma.
Kim YJ1,2, Yoo JE2,3,4, Jeon Y2, Uk Chong J5, Choi GH5, Song DG6, Jung SH1, Oh BK7, Park YN2,3,4.
1Natural Products Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, Korea.2Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.3Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.4Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.5Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.6Systems Biotechnology Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, Korea.7Institute of Medical Science, Hanyang University College of Medicine, Seoul, Korea.
Somatic mutations in the telomerase reverse transcriptase (TERT) promoter are related to telomerase activation and frequently occur at two hot spots located at -124 and -146 bp relative to the start codon in various cancers. Here, we investigated the occurrence and implications of genetic alterations in the TERT promoter in hepatitis B viral hepatocellular carcinoma (B viral HCC). TERT promoter mutations, especially -124C>T, clearly enhanced transcriptional activity in HCC cell lines. In contrast, TERT mRNA expression was lower in B viral HCC patients with TERT promoter mutations than in those without. We identified prospero homeobox protein 1 (PROX1) as a novel transcriptional activator of TERT; this protein was shown to have particularly strong binding affinity for the mutant TERT promoter. However, stable expression of the hepatitis B virus X (HBx) protein inhibited PROX1-mediated TERT expression in vitro. Our data suggest that TERT promoter mutations can enhance the promoter activity in HCC cell lines expressing PROX1 but are not the predominant mechanism of TERT upregulation in B viral HCC patients, based on the inhibition of PROX1-dependent transcriptional activation by HBx. This article is protected by copyright. All rights reserved.