Griffith Institute for Health and Medical Research, Griffith University, Gold Coast Campus, Southport, QLD, Australia.
Int J Cancer. 2011 Apr 15;128(8):1783-92. doi: 10.1002/ijc.25506.
Transforming growth factor-β1 (TGF-β1) induces stromal fibroblast-to-myofibroblast transdifferentiation in the tumor-stroma interactive microenvironment via modulation of multiple phenotypic and functional genes, which plays a critical role in tumor progression. Up to now, the involvement of micro-RNAs (miRNAs) and their roles in TGF-β1-induced myofibroblast differentiation in tumor-stroma interaction are unclear. Using quantitative real-time RT-PCR, we demonstrated that the expression of micro-RNA-21 (miR-21) was upregulated in activated fibroblasts after treatment with TGF-β1 or conditioned medium from cancer cells. To determine the potential roles of miR-21 in TGF-β1-mediated gene regulation during myofibroblast conversion, we showed that miR-21 expression was downregulated by miR-21 inhibitor and upregulated by miR-21 mimic. Interestingly, downregulation of miR-21 with the inhibitor effectively inhibited TGF-β1-induced myofibroblast differentiation while upregulation of miR-21 with a mimic significantly promoted myofibroblast differentiation. We further demonstrated that MiR-21 directly targeted and downregulated programmed cell death 4 (PDCD4) gene, which in turn acted as a negative regulator of several phenotypic and functional genes of myofibroblasts. Taken together, these results suggested that miR-21 participated in TGF-β1-induced myofibroblast transdifferentiation in cancer stroma by targeting PDCD4.
转化生长因子-β1（TGF-β1）通过调节多种表型和功能基因，在肿瘤-基质相互作用的微环境中诱导基质成纤维细胞向肌成纤维细胞的转分化，在肿瘤进展中起着关键作用。到目前为止，miRNAs 的参与及其在肿瘤-基质相互作用中 TGF-β1 诱导的肌成纤维细胞分化中的作用尚不清楚。我们使用定量实时 RT-PCR 证明，在 TGF-β1 或癌细胞条件培养基处理后，活化的成纤维细胞中 microRNA-21（miR-21）的表达上调。为了确定 miR-21 在 TGF-β1 介导的肌成纤维细胞转化过程中的基因调控中的潜在作用，我们表明 miR-21 表达被 miR-21 抑制剂下调，被 miR-21 模拟物上调。有趣的是，miR-21 抑制剂的下调有效抑制了 TGF-β1 诱导的肌成纤维细胞分化，而 miR-21 模拟物的上调则显著促进了肌成纤维细胞分化。我们进一步证明，miR-21 直接靶向并下调程序性细胞死亡因子 4（PDCD4）基因，而 PDCD4 基因反过来作为肌成纤维细胞的几个表型和功能基因的负调节剂。总之，这些结果表明，miR-21 通过靶向 PDCD4 参与 TGF-β1 诱导的肿瘤基质中的肌成纤维细胞转分化。
