| HIF-2α inhibits hepatocellular carcinoma growth through the TFDP3/E2F1-dependent apoptotic pathway. | |
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MedLine Citation:
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PMID: 23212661 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Hypoxia inducible factors (HIFs) are activated in many tumors and show either promoter or suppressor activity depending on the tumor cell biology and background. However, the role of HIF member HIF-2α remains unclear in hepatocellular carcinoma (HCC). Here, HIF-2α expression was measured in HCC and paired peritumoral tissues by qRT-PCR, western blot analysis, and immunofluorescence assays, and the clinical significance was explored in 246 HCC patients. In cell culture, HIF-2α levels were over-expressed or knocked-down by use of expression or short hairpin RNA recombinant plasmid respectively. Cells were analyzed by immunoblot, chromatin immunoprecipitation coupled with microarray, co-immunoprecipitation, and histochemical staining. In vivo tumor growth was analyzed in nude mice. We found that the average expression of HIF-2α was relatively low in HCC tissues, and the decreased level was associated with lower overall survival (p=0.006). High HIF-2α expression in HCC cells induced higher levels of apoptosis and expression of pro-apoptotic proteins, and it inhibited cell and tumor growth. Furthermore, HIF-2α inhibited expression of the novel target gene transcription factor dimerization partner 3 (TFDP3). TFDP3 protein was found to bind with E2F transcription factor 1 (E2F1) and inhibit its transcriptional activity through both p53-dependent and -independent pathways. Re-introduction of TFDP3 expression reversed HIF-2α-induced apoptosis. Conclusions: Data gathered from cell lines, tumorigenicity studies, and primary HCC samples demonstrate a negative role of HIF-2α in tumors, which is mediated by the TFDP3/E2F1 pathway. Our study provides evidence supporting a possible tumor suppressor role for HIF-2α and has uncovered a mechanism that links HIF-2α to a fundamental biological regulator, E2F1. (HEPATOLOGY 2012.). |
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Authors:
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Hai-Xiang Sun; Yang Xu; Xin-Rong Yang; Wei-Min Wang; Haibo Bai; Ruo-Yu Shi; Suresh K Nayar; Ranjan Prasad Devbhandari; Yi-Zhou He; Qin-Feng Zhu; Yun-Fan Sun; Bo Hu; Mehtab Khan; Robert A Anders; Jia Fan |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-12-5 |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: - ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-5 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 American Association for the Study of Liver Diseases. |
Affiliation:
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Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai 200032, P. R. China; The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Division of Gastrointestinal and Liver Pathology, Baltimore, MD 21205, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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