Li Pu, Shan Jing-Xuan, Chen Xue-Hua, Zhang Di, Su Li-Ping, Huang Xiu-Ying, Yu Bei-Qin, Zhi Qiao-Ming, Li Cheng-Long, Wang Ya-Qing, Tomei Sara, Cai Qu, Ji Jun, Li Jian-Fang, Chouchane Lotfi, Yu Ying-Yan, Sun Fang-Zhen, Xu Zhi-Heng, Liu Bing-Ya, Zhu Zheng-Gang
Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Ruijin Er Rd, Shanghai 200025, China.
Laboratory of Genetic Medicine and Immnology, Weill Cornell Medical College in Qatar, Education City, P.O. Box 24144, Doha, Qatar.
Cell Res. 2015 May;25(5):588-603. doi: 10.1038/cr.2015.51. Epub 2015 Apr 28.
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.
肿瘤的起始和生长依赖于其微环境，其中肿瘤基质中的癌症相关成纤维细胞（CAFs）发挥着重要作用。前列腺素E2（PGE2）和白细胞介素（IL）-6信号通路参与肿瘤细胞与基质细胞之间的相互作用。然而，PGE2介导的信号如何调节这种相互作用仍不清楚。在此，我们表明，微小RNA（miR）-149在介导胃癌（GC）肿瘤细胞与CAFs之间的相互作用中连接了PGE2和IL-6信号。miR-149通过靶向IL-6抑制成纤维细胞活化，并且在GC的CAFs中miR-149表达被显著抑制。miR-149在体外和体内均负向调节CAFs及其对GC发展的影响。CAFs以miR-149-IL-6依赖的方式增强GC细胞的上皮-间质转化（EMT）和干细胞样特性。除IL-6外，前列腺素E2受体2（PTGER2/EP2）被揭示为成纤维细胞中miR-149的另一个潜在靶点。此外，幽门螺杆菌感染是人类GC的主要病因，能够诱导环氧化酶-2（COX-2）/PGE2信号并增强PGE2产生，导致CAFs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GC中肿瘤细胞与CAFs之间的相互作用，并突出了干扰基质细胞中微小RNA以改善癌症治疗的潜力。
