Hypoxia‐inhibited DUSP2 expression promotes IL‐6/STAT3 signaling in endometriosis

Kuei‐Yang Hsiao, Ning Chang, Jia-Ling Tsai, Jia‐Ling Tsai, Shih-Chieh Lin, Shih‐Chieh Lin, Shaw-Jenq Tsai, Shaw‐Jenq Tsai, Meng‐Hsing Wu, Meng-Hsing Wu
American journal of reproductive immunology (New York, N.Y. : 1989) · 2017 · vol. 78(4) · doi:10.1111/aji.12690 · PMID:28440564 · W2607605940
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Abstract

PROBLEM: How does hypoxia-mediated downregulation of dual-specificity phosphatase-2 (DUSP2) promote the development of endometriotic lesions? METHOD OF STUDY: The levels of IL-6 and DUSP2 were assessed in eutopic stromal cells with DUSP2 knockdown or hypoxia treatment. Bromodeoxyuridine (BrdU) incorporation was applied for evaluating cell proliferation. The protein levels of DUSP2, cleaved caspase-3, phosphorylated STAT3, and STAT3 were analyzed using immunoblot. RESULTS: The genomewide analysis of cells with DUSP2 overexpression indicated IL-6 regulates multiple pathways related to inflammation, proliferation, and apoptosis. DUSP2 overexpression significantly suppressed IL-6 expression, while DUSP2 knockdown promoted IL-6 expression. The hypoxia-treated eutopic stromal cells expressed higher levels of IL-6, recapitulating the elevated levels of IL-6 in ectopic stromal cells. The treatment with IL-6 elicited the phosphorylation of STAT3, mimicking the elevated levels of phosphorylated STAT3 in the ectopic stromal cells. The IL-6-treated eutopic stromal cells showed more BrdU incorporation and less cleaved caspase-3, which can be reversed by STAT3 inhibitor. CONCLUSION: Hypoxia-induced IL-6 production in endometriotic lesions is mediated via downregulation of DUSP2, which causes aberrant activation of STAT3 signaling pathway and helps the endometriotic cells survive under the ectopic environment.

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mesh:D004715endometriosis

MeSH descriptors

Dual Specificity Phosphatase 2 Endometriosis Endometrium Hypoxia Interleukin-6 STAT3 Transcription Factor Stromal Cells Adolescent Adult Apoptosis Caspase 3 Caspase 3 Cells, Cultured Child Choristoma Dual Specificity Phosphatase 2 Dual Specificity Phosphatase 2 Endometriosis Endometriosis Endometrium

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