GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1β/IL1R1 response.
GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1β/IL1R1 response.
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DOI：
10.1038/srep24354
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发表时间：
2016-04-13
影响因子：
4.6
通讯作者：
Maggiolini M
中科院分区：
文献类型：
--
作者：
De Marco P;Lappano R;De Francesco EM;Cirillo F;Pupo M;Avino S;Vivacqua A;Abonante S;Picard D;Maggiolini M
癌症相关成纤维细胞 (CAF) 通过 IL1β 等分泌因子促进恶性侵袭，IL1β 可能主要通过名为 IL1R1 的同源受体驱动促肿瘤炎症表型。在这里，我们证明由 G 蛋白雌激素受体 (GPER) 介导的信号传导分别触发 CAF 和乳腺癌细胞中的 IL1β 和 IL1R1 表达。因此，GPER 的配体激活产生前馈环，将 CAF 诱导的 IL1β 与癌细胞表达的 IL1R1 耦合，促进 IL1β/IL1R1 靶基因（如 PTGES、COX2、RAGE 和 ABCG2）的上调。两种细胞类型之间的这种调节相互作用诱导乳腺癌细胞的迁移和侵袭特征，包括成纤维细胞结构和 F-肌动蛋白重组。更好地了解 GPER 整合雌激素信号调节促炎细胞因子的机制可能有助于靶向这些基质癌相互作用。
Cancer-associated fibroblasts (CAFs) contribute to the malignant aggressiveness through secreted factors like IL1β, which may drive pro-tumorigenic inflammatory phenotypes mainly acting via the cognate receptor named IL1R1. Here, we demonstrate that signalling mediated by the G protein estrogen receptor (GPER) triggers IL1β and IL1R1 expression in CAFs and breast cancer cells, respectively. Thereby, ligand-activation of GPER generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, promoting the up-regulation of IL1β/IL1R1 target genes such as PTGES, COX2, RAGE and ABCG2. This regulatory interaction between the two cell types induces migration and invasive features in breast cancer cells including fibroblastoid cytoarchitecture and F-actin reorganization. A better understanding of the mechanisms involved in the regulation of pro-inflammatory cytokines by GPER-integrated estrogen signals may be useful to target these stroma-cancer interactions.