title: Hypoxia inducible factor 2 alpha inhibits hepatocellular carcinoma growth through the transcription factor dimerization partner 3/ E2F transcription factor 1-dependent apoptotic pathway.
abstract: Hypoxia inducible factors (HIFs) are activated in many tumors and show either promoter or suppressor activity, depending on 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 quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence assays, and the clinical significance was explored in 246 HCC patients. In cell culture, HIF-2α levels were up-regulated or down-regulated by use of expression or short hairpin RNA recombinant plasmid, respectively. Cells were analyzed by immunoblotting, chromatin immunoprecipitation coupled with microarray, coimmunoprecipitation, and immunohistochemical 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 proapoptotic proteins and 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. Reintroduction 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.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
authors.forename: Hai-Xiang
authors.initials: HX
authors.lastname: Sun
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Xin-Rong
authors.initials: XR
authors.lastname: Yang
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Wang
authors.forename: Haibo
authors.initials: H
authors.lastname: Bai
authors.forename: Ruo-Yu
authors.initials: RY
authors.lastname: Shi
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Nayar
authors.forename: Ranjan P
authors.initials: RP
authors.lastname: Devbhandari
authors.forename: Yi-zhou
authors.initials: YZ
authors.lastname: He
authors.forename: Qin-Feng
authors.initials: QF
authors.lastname: Zhu
authors.forename: Yun-Fan
authors.initials: YF
authors.lastname: Sun
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Mehtab
authors.initials: M
authors.lastname: Khan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008819:Mice, Nude; D050680:Transcription Factor DP1 / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050687:E2F1 Transcription Factor; D050680:Transcription Factor DP1; D000099162:Endothelial PAS Domain-Containing Protein 1; C493753:E2F1 protein, human; C516920:TFDP3 protein, human