RRC ID 28472
Author Yoshida T, Hashimura M, Mastumoto T, Tazo Y, Inoue H, Kuwata T, Saegusa M.
Title Transcriptional upregulation of HIF-1α by NF-κB/p65 and its associations with β-catenin/p300 complexes in endometrial carcinoma cells.
Journal Lab Invest
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.
Volume 93(11)
Pages 1184-93
Published 2013-11-1
DOI 10.1038/labinvest.2013.111
PII labinvest2013111
PMID 24042437
MeSH Cell Hypoxia / genetics Cell Hypoxia / physiology Cell Line, Tumor E1A-Associated p300 Protein / chemistry E1A-Associated p300 Protein / metabolism* Endometrial Neoplasms / genetics* Endometrial Neoplasms / metabolism* Endometrial Neoplasms / pathology Female Gene Expression Regulation, Neoplastic Humans Hypoxia-Inducible Factor 1, alpha Subunit / genetics* Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* Immunohistochemistry In Situ Hybridization Multiprotein Complexes / chemistry Multiprotein Complexes / metabolism RNA, Messenger / genetics RNA, Messenger / metabolism RNA, Neoplasm / genetics RNA, Neoplasm / metabolism Transcription Factor RelA / genetics Transcription Factor RelA / metabolism* Up-Regulation beta Catenin / chemistry beta Catenin / metabolism*
IF 4.197
Times Cited 31
DNA material pCMFlag_hsHIF1A (RDB06378)