子宫内膜癌
雌激素
雌激素受体
癌症研究
川地68
医学
癌症
内科学
下调和上调
雌激素受体α
炎症
内分泌学
乳腺癌
生物
免疫组织化学
生物化学
基因
作者
Chengcheng Ning,Bingying Xie,Lin Zhang,Chunsheng Li,Weiwei Shan,Bingyi Yang,Xuezhen Luo,Chao Gu,Qizhi He,Hongyan Jin,Xiaojun Chen,Zhenbo Zhang,Youji Feng
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2016-01-12
卷期号:76 (6): 1354-1366
被引量:64
标识
DOI:10.1158/0008-5472.can-15-1260
摘要
Abstract Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68+CD163+ macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERα), but not ERβ. Mechanistic investigations revealed that CD68+CD163+ macrophages secreted cytokines, such as IL17A, that upregulated ERα expression through TET1-mediated epigenetic modulation of the ERα gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERα expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting. Cancer Res; 76(6); 1354–66. ©2016 AACR.
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