TY - JOUR
T1 - Aberrant expression of leptin in human endometriotic stromal cells is induced by elevated levels of hypoxia inducible factor-1α
AU - Wu, Meng Hsing
AU - Chen, Ko Fan
AU - Lin, Shih Chieh
AU - Lgu, Chun Wun
AU - Tsai, Shaw Jenq
N1 - Funding Information:
Supported by grant NSC 93-2314-B-006-073 from the National Science Council (to M.-H.W.) and grant NSC94-3112-B-006-010 from the National Research Program for Genomic Medicine (to S.-J.T.), Taiwan, Republic of China.
PY - 2007/2
Y1 - 2007/2
N2 - Elevated expression of leptin in endometriotic tissue results in an increase in stromal cell proliferation and may contribute to the development of endometriosis. However, the underlying mechanism responsible for aberrant expression of leptin is not known. We hypothesize that aberrant expression of leptin in endometriotic stroma may be regulated by increased levels of hypoxia-inducible factor-1α (HEF-1α), the master transcription factor that controls gene expression in response to hypoxia. Herein we show that the mRNA and protein levels of HIF-1α were greater in ectopic endometriotic tissue compared with its eutopic counterpart. Exposure of eutopic endometrial stromal cells under hypoxic conditions or treated with desferrioxamine (DFO, chemical hypoxia) resulted in a time-dependent increase in leptin gene expression. A promoter activity assay demonstrated that HIF-1α induced leptin promoter activity after DFO treatment. Chromatin immunoprecipitation assay further demonstrated that binding of HEF-1α to leptin promoter was evident after DFO treatment. Finally, depletion of HEF-1α by short interference RNA abolished leptin expression in ectopic endometriotic stromal cells. Taken together, our data demonstrate that aberrant expression of leptin in ectopic endometriotic stromal cells is induced, at least in part, by an elevated level of HEF-1α in these cells, providing new insights into the etiology of endometriosis.
AB - Elevated expression of leptin in endometriotic tissue results in an increase in stromal cell proliferation and may contribute to the development of endometriosis. However, the underlying mechanism responsible for aberrant expression of leptin is not known. We hypothesize that aberrant expression of leptin in endometriotic stroma may be regulated by increased levels of hypoxia-inducible factor-1α (HEF-1α), the master transcription factor that controls gene expression in response to hypoxia. Herein we show that the mRNA and protein levels of HIF-1α were greater in ectopic endometriotic tissue compared with its eutopic counterpart. Exposure of eutopic endometrial stromal cells under hypoxic conditions or treated with desferrioxamine (DFO, chemical hypoxia) resulted in a time-dependent increase in leptin gene expression. A promoter activity assay demonstrated that HIF-1α induced leptin promoter activity after DFO treatment. Chromatin immunoprecipitation assay further demonstrated that binding of HEF-1α to leptin promoter was evident after DFO treatment. Finally, depletion of HEF-1α by short interference RNA abolished leptin expression in ectopic endometriotic stromal cells. Taken together, our data demonstrate that aberrant expression of leptin in ectopic endometriotic stromal cells is induced, at least in part, by an elevated level of HEF-1α in these cells, providing new insights into the etiology of endometriosis.
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U2 - 10.2353/ajpath.2007.060477
DO - 10.2353/ajpath.2007.060477
M3 - Article
C2 - 17255327
AN - SCOPUS:33947522544
VL - 170
SP - 590
EP - 598
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 2
ER -