Aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling in endometriosis.
OBJECTIVE
Are STAT3 signaling molecules differentially expressed in endometriosis?


CONCLUSIONS
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.


BACKGROUND
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.


METHODS
Cross-sectional measurements of STAT3 and HIF1A protein levels in eutopic endometrium from women with endometriosis versus those without.


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.


RESULTS
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.


CONCLUSIONS
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.


CONCLUSIONS
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.


BACKGROUND
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.
Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA.
Byung Gak
BG
Kim
Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA.
Jung-Yoon
JY
Yoo
Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA.
Tae Hoon
TH
Kim
Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, Guro Hospital, Korea University Medical Center, Seoul 152-703, South Korea.
Jung-Ho
JH
Shin
Obstetrics and Gynecology, University Medical Group, Greenville Health System, Greenville, SC 29605, USA.
John F
JF
Langenheim
Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA.
Susan D
SD
Ferguson
Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA.
Asgerally T
AT
Fazleabas
Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC 27514, USA.
Steven L
SL
Young
Obstetrics and Gynecology, University Medical Group, Greenville Health System, Greenville, SC 29605, USA blessey@ghs.org jeongj@msu.edu.
Bruce A
BA
Lessey
Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA blessey@ghs.org jeongj@msu.edu.
Jae-Wook
JW
Jeong
D000293:Adolescent; D000328:Adult; D000818:Animals; D001706:Biopsy; D045744:Cell Line, Tumor; D003430:Cross-Sectional Studies; D004715:Endometriosis / Q000378:metabolism*; D004717:Endometrium / Q000378:metabolism*; D004958:Estradiol / Q000737:chemistry; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood; D008875:Middle Aged; D010215:Papio; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004958:Estradiol
HIF1A; IL6; STAT3; endometriosis