Molecular Targeting Unit, Research Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Biochemistry Department, Instituto Nacional de Ciencias Médicas y Nutriciòn Salvador Zubirán, Mexico City 14080, Mexico.
Cells. 2020 Sep 22;9(9):2143. doi: 10.3390/cells9092143.
Tumor growth and invasion occurs through a dynamic interaction between cancer and stromal cells, which support an aggressive niche. MicroRNAs are thought to act as tumor messengers to "corrupt" stromal cells. We previously demonstrated that miR-9, a known metastamiR, is released by triple negative breast cancer (TNBC) cells to enhance the transition of normal fibroblasts (NFs) into cancer-associated fibroblast (CAF)-like cells. EGF containing fibulin extracellular matrix protein 1 (), which encodes for the ECM glycoprotein fibulin-3, emerged as a miR-9 putative target upon miRNA's exogenous upmodulation in NFs. Here we explored the impact of downmodulation on fibroblast's acquisition of CAF-like features, and how this phenotype influences neoplastic cells to gain chemoresistance. Indeed, upon miR-9 overexpression in NFs, resulted downmodulated, both at RNA and protein levels. The luciferase reporter assay showed that miR-9 directly targets and its silencing recapitulates miR-9-induced pro-tumoral phenotype in fibroblasts. In particular, siRNA-transfected (si-) fibroblasts have an increased ability to migrate and invade. Moreover, TNBC cells conditioned with the supernatant of NFs transfected with miR-9 or si- became more resistant to cisplatin. Overall, our results demonstrate that miR-9/ axis is crucial for the conversion of NFs to CAF-like cells under TNBC signaling.
肿瘤的生长和侵袭是通过癌症和基质细胞之间的动态相互作用发生的，这种相互作用支持了一个侵袭性的生态位。microRNAs 被认为是肿瘤信使，能够“腐化”基质细胞。我们之前的研究表明，miR-9 是一种已知的转移 miRNA，它可以被三阴性乳腺癌（TNBC）细胞释放出来，促进正常成纤维细胞（NFs）向癌相关成纤维细胞（CAF）样细胞的转化。含有表皮生长因子的纤维连接蛋白细胞外基质蛋白 1（），它编码 ECM 糖蛋白纤维连接蛋白-3，在 NF 中外源上调 miRNA 时，成为 miR-9 的一个假定靶标。在这里，我们探讨了下调对成纤维细胞获得 CAF 样特征的影响，以及这种表型如何影响肿瘤细胞获得化疗耐药性。事实上，在 NF 中过表达 miR-9 后，和在 RNA 和蛋白水平上均下调。荧光素酶报告基因检测表明，miR-9 直接靶向并沉默其可再现 miR-9 诱导的成纤维细胞中促肿瘤表型。具体来说，转染了 miR-9 沉默 RNA（siRNA）的成纤维细胞（si-）具有更强的迁移和侵袭能力。此外，用 miR-9 或 si-转染的 NF 上清液处理的 TNBC 细胞对顺铂的耐药性增加。总之，我们的结果表明，miR-9/ 轴在 TNBC 信号转导下 NF 向 CAF 样细胞转化中至关重要。
