title: Transcriptional upregulation of HIF-1α by NF-κB/p65 and its associations with β-catenin/p300 complexes in endometrial carcinoma cells.
abstract: The hypoxia-inducible factor (HIF)-1α, which has a major role in cell adaptation to hypoxia, is mainly regulated at post-translational levels. Recently, HIF-1α mRNA was also shown to be upregulated by several signal pathways under normoxic conditions. Here we focused on relationships of HIF-1α with NF-κB and β-catenin signaling in endometrial carcinomas (Em Cas). Long-term exposure of Ishikawa cells to cobalt chloride (CoCl2), which is known to mimic the effect of hypoxia, caused a decrease in the growth, along with increased HIF-1α protein but not mRNA expression. In contrast, short-term exposure resulted in a rapid and transient increase in HIF-1α mRNA expression along with stabilization of nuclear NF-κB/p65 (p65). Transfection of p65 increased HIF-1α expression through activation of the promoter, whereas overexpression of HIF-1α also activated NF-κB-dependent transcription, indicating the existence of a positive feedback loop. In addition, HIF-1α was indirectly associated with nuclear β-catenin through interactions with p300, leading to slight enhancement of both HIF-1α- and β-catenin-mediated transcriptional activity. In clinical samples, biphasic upregulation of HIF-1α expression was observed in normal endometrial glandular components during the menstrual cycle, with the labeling indices showing significantly higher values in the early secretory stage. Significantly higher values for phosphorylated p65 and nuclear β-catenin were also observed in HIF-1α-positive than -negative lesions of Em Cas, in contrast to significantly lower Ki-67 status. These data therefore suggest that transcriptional associations with HIF-1α and NF-κB, as well as β-catenin/p300 complexes, may contribute to modulation of changes in tumor cell kinetics in response to a hypoxic condition in Em Cas.
authors.affiliation: Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshida
authors.forename: Miki
authors.initials: M
authors.lastname: Hashimura
authors.forename: Toshihide
authors.initials: T
authors.lastname: Mastumoto
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tazo
authors.forename: Hisako
authors.initials: H
authors.lastname: Inoue
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuwata
authors.forename: Makoto
authors.initials: M
authors.lastname: Saegusa
mesh_terms: D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000737:chemistry / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046912:Multiprotein Complexes; C498143:RELA protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051996:Transcription Factor RelA; D051176:beta Catenin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human