Aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling in endometriosis

Byung Gak Kim, Jung-Yoon Yoo, Jung‐Yoon Yoo, Tae Hoon Kim, Jung-Ho Shin, Jung‐Ho Shin, John F Langenheim, Susan D Ferguson, Asgerally T Fazleabas, Steven L Young, Bruce A Lessey, Jae-Wook Jeong, Jae‐Wook Jeong
Human Reproduction · 2015 · vol. 30(5) , pp. 1069–1078 · doi:10.1093/humrep/dev050 · PMID:25750101 · PMC4400199 · W2161681862
article OA: bronze CC0 ⤵ 71 in-corpus citations
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Phospho-STAT3 and its downstream molecule HIF1A are significantly elevated in eutopic endometrium from women with endometriosis compared to controls, suggesting aberrant STAT3 activation in the disease.

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Abstract

STUDY QUESTION: Are STAT3 signaling molecules differentially expressed in endometriosis? SUMMARY ANSWER: Levels of phospho-STAT3 and HIF1A, its downstream signaling molecule, are significantly higher in eutopic endometrium from women with endometriosis when compared with women without the disease. WHAT IS KNOWN ALREADY: Endometriosis is an estrogen-dependent inflammatory condition. Interleukin 6 (IL-6) is an inflammatory survival cytokine known to induce prolonged activation of STAT3 via association with the IL-6 receptor. STUDY DESIGN, SIZE, DURATION: Cross-sectional measurements of STAT3 and HIF1A protein levels in eutopic endometrium from women with endometriosis versus those without. PARTICIPANTS/MATERIALS, SETTING, METHODS: Levels of phospho-STAT3 (pSTAT3) and HIF1A were examined in the endometrium of patients with and without endometriosis as well as in a non-human primate animal model using western blot and immunohistochemical analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Levels of pSTAT3 were significantly higher in the eutopic endometrium from women with endometriosis when compared with women without the disease in both the proliferative and secretory phases. HIF1A is known to be stabilized by STAT3 and IL-6. Our immunohistochemistry results show abundant HIF1A expression within the eutopic endometrial epithelial cells of women with endometriosis. Furthermore, pSTAT3 and HIF1A proteins are co-localized in endometriosis. This aberrant activation of pSTAT3 and HIF1A is confirmed by sequential analysis of eutopic endometrium using a baboon animal model of induced endometriosis. Lastly, we confirmed this IL-6 induction of both STAT3 phosphorylation and HIF1A mRNA expression in Ishikawa human endometrial adenocarcinoma cell line. LIMITATIONS, REASONS FOR CAUTION: Ishikawa cancer cell line was used to study a benign disease. The peritoneal fluid contains various inflammatory cytokines in addition to IL-6 and so it is possible that other cytokines may affect the activity and expression of STAT3 signaling molecules. WIDER IMPLICATIONS OF THE FINDINGS: Our results imply that aberrant activation of STAT3 signaling plays an important role in the pathogenesis of endometriosis. Our findings could progress in our understanding of the etiology and pathophysiology of endometriosis and potential therapeutic interventions by targeted pharmacological. STUDY FUNDING/COMPETING INTERESTS: This work was supported by NIH R01 HD067721 (to S.L.Y and B.A.L) and NIH R01 HD057873 and American Cancer Society Research Grant RSG-12-084-01-TBG (to J.-W.J.). There are no conflicts of interest.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometrium Hypoxia-Inducible Factor 1, alpha Subunit STAT3 Transcription Factor Adolescent Adult Animals Biopsy Cell Line, Tumor Cross-Sectional Studies Endometriosis Endometrium Estradiol Estradiol Female Gene Expression Profiling Gene Expression Regulation Humans Hypoxia-Inducible Factor 1, alpha Subunit Hypoxia-Inducible Factor 1, alpha Subunit

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