Hypoxia-inhibited DUSP2 expression promotes IL-6/STAT3 signaling in endometriosis
Hypoxia-inhibited DUSP2 expression promotes IL-6/STAT3 signaling in endometriosis
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DOI：
10.1111/aji.12690
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发表时间：
2017-10-01
影响因子：
3.6
通讯作者：
Wu, Meng-Hsing
中科院分区：
文献类型：
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作者：
Hsiao, Kuei-Yang;Chang, Ning;Wu, Meng-Hsing
问题：缺氧介导的双特异性磷酸酶-2 (DUSP2) 下调如何促进子宫内膜异位病变的发展？研究方法：通过 DUSP2 敲低或缺氧治疗，评估在位基质细胞中 IL-6 和 DUSP2 的水平。溴脱氧尿苷（BrdU）掺入用于评估细胞增殖。使用免疫印迹分析 DUSP2、裂解的 caspase-3、磷酸化 STAT3 和 STAT3 的蛋白水平。结果：对 DUSP2 过表达的细胞进行全基因组分析表明 IL-6 调节与炎症、增殖和凋亡相关的多种途径。 DUSP2过表达显着抑制IL-6表达，而DUSP2敲低则促进IL-6表达。缺氧处理的在位基质细胞表达更高水平的IL-6，概括了异位基质细胞中升高的IL-6水平。 IL-6 处理引发 STAT3 磷酸化，模拟异位基质细胞中磷酸化 STAT3 水平的升高。 IL-6处理的在位基质细胞表现出更多的BrdU掺入和更少的caspase-3裂解，这可以被STAT3抑制剂逆转。结论：缺氧诱导的子宫内膜异位病灶中IL-6的产生是通过DUSP2的下调介导的，从而导致STAT3信号通路的异常激活，帮助子宫内膜异位细胞在异位环境下生存。
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.