A20-mediated deubiquitination of ERα in the microenvironment of CD163+ macrophages sensitizes endometrial cancer cells to estrogen
A20-mediated deubiquitination of ERα in the microenvironment of CD163+ macrophages sensitizes endometrial cancer cells to estrogen
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CD163 巨噬细胞微环境中 A20 介导的 ERα 去泛素化使子宫内膜癌细胞对雌激素敏感
DOI：
10.1016/j.canlet.2018.10.019
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发表时间：
2019-02-01
期刊：
影响因子：
9.7
通讯作者：
Xu, Congjian
中科院分区：
文献类型：
--
作者：
Lv, Qiaoying;Xie, Liying;Xu, Congjian
持续的雌激素信号被认为是导致子宫内膜癌的主要机制。研究表明CD163（+）巨噬细胞可促进雌激素依赖性EC的发展，但其机制尚不清楚。我们发现CD163（+）巨噬细胞是不典型子宫内膜增生和癌中的显性巨噬细胞，其浸润与ER α表达呈正相关。CD163（+）巨噬细胞主要上调ERa蛋白水平，但对ESR1 （ER α编码基因）转录本的上调作用不大。从接受高脂肪饮食和持续雌激素干预的小鼠子宫内膜微阵列中筛选的泛素编辑酶A20在富含CD163（+）巨噬细胞的子宫内膜病变中高表达，并与ER α表达呈正相关。同样，CD163（+）巨噬细胞通过ILla、IL17A和TNF α等细胞因子上调A20和ER α。从机制上讲，EC细胞中A20的过表达延长了ER α蛋白的半衰期，但不影响ESR1转录本。A20通过其去泛素酶活性阻止ER α蛋白降解，从而提高功能性ER α蛋白水平，增强雌激素驱动的EC细胞增殖。我们的研究表明，a20介导的ER α去泛素化可能是CD163（+）巨噬细胞使EC细胞对雌激素敏感的重要机制。
Continuous estrogen signaling is thought to be the main mechanism causing endometrial cancer (EC). Studies have demonstrated that CD163(+) macrophages could promote the development of estrogen-dependent EC, but the mechanisms involved remain unclear. We found that CD163(+) macrophages were the dominant macrophages in atypical endometrial hyperplasia and cancer, and their infiltration was positively associated with ER alpha expression. CD163(+) macrophages mainly increased ERa protein levels but with little upregulatory effect on ESR1 (ER alpha coding gene) transcripts. The ubiquitin-editing enzyme A20, screened from the endometrial microarray obtained from mice receiving a high-fat diet and sustained estrogen-intervened, was highly expressed in endometrial lesions rich with CD163(+) macrophages, and positively correlated with ER alpha expression. Similarly, A20 and ER alpha were both upregulated by CD163(+) macrophages via cytokines such as ILla, IL17A and TNF alpha. Mechanistically, A20 overexpression in EC cells prolonged ER alpha protein half-life without affecting ESR1 transcripts. A20 increased functional ER alpha protein levels and enhanced estrogen-driven EC cell proliferation through preventing ER alpha protein degradation by its deubiquitinase activity. Our study revealed that A20-mediated deubiquitination of ER alpha might be an important mechanism by which CD163(+) macrophages sensitize EC cells to estrogen.