Kim Byung Gak, Yoo Jung-Yoon, Kim Tae Hoon, Shin Jung-Ho, Langenheim John F, Ferguson Susan D, Fazleabas Asgerally T, Young Steven L, Lessey Bruce A, Jeong Jae-Wook
Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA.
Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, Guro Hospital, Korea University Medical Center, Seoul 152-703, South Korea.
Hum Reprod. 2015 May;30(5):1069-78. doi: 10.1093/humrep/dev050. Epub 2015 Mar 6.
Are STAT3 signaling molecules differentially expressed in endometriosis?
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.
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.
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.
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.
信号转导和转录激活因子3（STAT3）信号分子在子宫内膜异位症中是否存在差异表达？
与未患该疾病的女性相比，子宫内膜异位症女性的在位内膜中磷酸化STAT3及其下游信号分子缺氧诱导因子1α（HIF1A）的水平显著更高。
子宫内膜异位症是一种雌激素依赖性炎症性疾病。白细胞介素6（IL-6）是一种炎症存活细胞因子，已知其通过与IL-6受体结合诱导STAT3的长期激活。
研究设计、规模、持续时间：对患有和未患有子宫内膜异位症的女性的在位内膜中STAT3和HIF1A蛋白水平进行横断面测量。
研究对象/材料、环境、方法：使用蛋白质免疫印迹法和免疫组织化学分析，检测患有和未患有子宫内膜异位症的患者以及非人类灵长类动物模型的子宫内膜中磷酸化STAT3（pSTAT3）和HIF1A的水平。
在增殖期和分泌期，与未患该疾病的女性相比，子宫内膜异位症女性的在位内膜中pSTAT3水平显著更高。已知HIF1A可被STAT3和IL-6稳定。我们的免疫组织化学结果显示，子宫内膜异位症女性的在位内膜上皮细胞中有丰富的HIF1A表达。此外，pSTAT3和HIF1A蛋白在子宫内膜异位症中共定位。使用诱导性子宫内膜异位症的狒狒动物模型对在位内膜进行序贯分析，证实了pSTAT3和HIF1A的这种异常激活。最后，我们在石川人子宫内膜腺癌细胞系中证实了IL-6对STAT3磷酸化和HIF1A mRNA表达的诱导作用。
局限性、谨慎的原因：使用石川癌细胞系研究一种良性疾病。腹膜液中除了IL-6外还含有多种炎症细胞因子，因此其他细胞因子可能会影响STAT3信号分子的活性和表达。
我们的结果表明，STAT3信号的异常激活在子宫内膜异位症的发病机制中起重要作用。我们的发现可能会增进我们对子宫内膜异位症的病因和病理生理学的理解，以及通过靶向药理学进行潜在治疗干预的认识。
研究资金/利益冲突：本研究得到美国国立卫生研究院R01 HD067721（授予S.L.Y和B.A.L）、美国国立卫生研究院R01 HD057873以及美国癌症协会研究基金RSG-12-084-01-TBG（授予J.-W.J.）的支持。不存在利益冲突。
