title: Hypoxia induces hemorrhagic transformation in pituitary adenomas via             the HIF-1α signaling pathway.
abstract: The hypoxia inducible factor 1 α (HIF-1α) activity has been associated with             various hemorrhagic events. The biological role of HIF-1α in the hemorrhagic transformation             of pituitary adenomas remains unknown. We hypothesized that fast growing tumor             cells tend to predispose themselves to sublethal hypoxia and activate the HIF-1α             signaling pathway, leading to hemorrhagic transformation in pituitary adenomas.             Here, we used apoplectic and non-apoplectic pituitary adenomas to determine the             involvement of HIF-1α signaling in intratumoral hemorrhage. We employed HIF-1α             overexpression/knockdown strategies to examine the association between HIF-1α             signaling and hemorrhagic presentation in vitro and in vivo. In support of our             hypothesis, compared with non-hemorrhagic pituitary adenomas, higher cellular             proliferation was observed in hemorrhagic ones and it correlated with increased             HIF-1α signaling. HIF-1α overexpression activated its downstream genes, vascular             endothelial growth factor and the proapoptotic BNIP3, in MMQ pituitary adenoma             cells and this up-regulation was attenuated by HIF-1 siRNA. In vivo studies using             MMQ cell xenografts in nude mice showed that HIF-1α overexpression significantly             promoted hemorrhagic transformation. Our study indicates that tumor hypoxia, following             rapid tumor growth, may promote hemorrhagic transformation in pituitary adenomas             via the HIF-1α signaling pathway.
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Zhengzheng
authors.initials: Z
authors.lastname: Xiao
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.forename: Boxi
authors.initials: B
authors.lastname: Zhao
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Ting
authors.initials: T
authors.lastname: Lei
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D020300:Intracranial Hemorrhages / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010911:Pituitary Neoplasms / Q000378:metabolism / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055815:Young Adult
chemical_list: C090121:BNIP3 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A