Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling.
Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling.
复制标题
基质 miR-200 通过 CAF 激活和 ECM 重塑促进乳腺癌细胞侵袭
DOI：
10.1038/cdd.2015.78
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发表时间：
2016-01
影响因子：
12.4
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Tang X;Hou Y;Yang G;Wang X;Tang S;Du YE;Yang L;Yu T;Zhang H;Zhou M;Wen S;Xu L;Liu M
癌症相关成纤维细胞（CAFs）的激活是肿瘤进展的关键事件，来自CAFs的替代细胞外基质（ECM）蛋白诱导ECM重塑和癌细胞侵袭。我们发现mir - 200s在乳腺癌组织中活化的CAFs和被乳腺癌细胞激活的正常成纤维细胞（NFs）中普遍下调，是NF重编程为CAFs和ECM重塑的直接介质。mir - 200s下调的NFs表现出活化的CAFs的特征，包括加速迁移和侵袭。在CAFs中异位表达mir - 200s至少部分恢复了NFs的表型。CAF激活可能受mir - 200s、fl -1和TCF12的靶标调控，它们负责细胞的发育和分化；CAFs中Fli-1和TCF12明显升高。此外，mir - 200s及其靶标影响胶原蛋白的收缩。miR-200直接或通过fl -1或TCF12间接上调纤维连接蛋白和赖氨酸氧化酶，促进ECM重塑，在体外和体内触发乳腺癌细胞的侵袭和转移。因此，这些数据为触发肿瘤细胞侵袭的乳腺CAF激活和ECM重塑提供了重要而新颖的见解。
The activation of cancer-associated fibroblasts (CAFs) is a key event in tumor progression, and alternative extracellular matrix (ECM) proteins derived from CAFs induce ECM remodeling and cancer cell invasion. Here we found that miR-200 s, which are generally downregulated in activated CAFs in breast cancer tissues and in normal fibroblasts (NFs) activated by breast cancer cells, are direct mediators of NF reprogramming into CAFs and of ECM remodeling. NFs with downregulated miR-200 s displayed the traits of activated CAFs, including accelerated migration and invasion. Ectopic expression of miR-200 s in CAFs at least partially restored the phenotypes of NFs. CAF activation may be governed by the targets of miR-200 s, Fli-1 and TCF12, which are responsible for cell development and differentiation; Fli-1 and TCF12 were obviously elevated in CAFs. Furthermore, miR-200 s and their targets influenced collagen contraction by CAFs. The upregulation of fibronectin and lysyl oxidase directly by miR-200 or indirectly through Fli-1 or TCF12 contributed to ECM remodeling, triggering the invasion and metastasis of breast cancer cells both in vitro and vivo. Thus, these data provide important and novel insights into breast CAF activation and ECM remodeling, which trigger tumor cell invasion.