Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment.
Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment.
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癌症相关成纤维细胞中 microRNA-149 的表观遗传沉默介导肿瘤微环境中前列腺素 E2/白细胞介素 6 信号传导
作者：
肿瘤的发生和生长依赖于其微环境，肿瘤间质中的癌相关成纤维细胞（CAFs）在其中起着重要作用。前列腺素E2（PGE 2）和白细胞介素（IL）-6信号通路参与肿瘤和基质细胞之间的相互作用。然而，PGE 2介导的信号传导如何调节这种串扰仍不清楚。在这里，我们发现microRNA（miR）-149连接PGE 2和IL-6信号转导介导胃癌（GC）中肿瘤细胞和CAFs之间的串扰。miR-149通过靶向IL-6抑制成纤维细胞活化，并且miR-149在GC的CAFs中的表达基本上被抑制。miR-149在体外和体内负调控CAFs及其对GC发育的影响。CAF以miR-149-IL-6依赖的方式增强上皮向间充质转化（EMT）和GC细胞的干细胞样特性。除了IL-6之外，PGE 2受体2（PTGER 2/EP 2）被揭示为成纤维细胞中miR-149的另一个潜在靶点。此外，H. pylori感染是人类胃癌的主要病因，能够诱导环氧合酶-2（考克斯-2）/PGE 2信号传导并增强PGE 2的产生，导致CAF中miR-149的高甲基化和IL-6分泌增加。我们的研究结果表明，miR-149介导了胃癌中肿瘤细胞和CAFs之间的串扰，并强调了基质细胞中干扰miRNA改善癌症治疗的潜力。
Tumor initiation and growth depend on its microenvironment in which cancer-associated fibroblasts (CAFs) in tumor stroma play an important role. Prostaglandin E2 (PGE2) and interleukin (IL)-6 signal pathways are involved in the crosstalk between tumor and stromal cells. However, how PGE2-mediated signaling modulates this crosstalk remains unclear. Here, we show that microRNA (miR)-149 links PGE2 and IL-6 signaling in mediating the crosstalk between tumor cells and CAFs in gastric cancer (GC). miR-149 inhibited fibroblast activation by targeting IL-6 and miR-149 expression was substantially suppressed in the CAFs of GC. miR-149 negatively regulated CAFs and their effect on GC development both in vitro and in vivo. CAFs enhanced epithelial-to-mesenchymal transition (EMT) and the stem-like properties of GC cells in a miR-149-IL-6-dependent manner. In addition to IL-6, PGE2 receptor 2 (PTGER2/EP2) was revealed as another potential target of miR-149 in fibroblasts. Furthermore, H. pylori infection, a leading cause of human GC, was able to induce cyclooxygenase-2 (COX-2)/PGE2 signaling and to enhance PGE2 production, resulting in the hypermethylation of miR-149 in CAFs and increased IL-6 secretion. Our findings indicate that miR-149 mediates the crosstalk between tumor cells and CAFs in GC and highlight the potential of interfering miRNAs in stromal cells to improve cancer therapy.
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