The insulin-like growth factor (IGF)-1 and transforming growth factor (TGF)-β signal pathways are both recognized as important in regulating cancer prognosis, such as the epithelial-to-mesenchymal transition (EMT) and cell invasion. However, cross-talk between these two signal pathways in glioblastoma multiforme (GBM) is still unclear. In the present study, by analyzing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE) 4412, GBM patients with higher IGF-1 levels exhibited poorer survival. Genes positively correlated with IGF-1 were enriched in EMT and TGF-β signal pathways. IGF-1 treatment enhanced mesenchymal marker expressions and GBM cell invasion. A significant positive correlation was observed for IGF-1 with TGF-β1 (TGFB1) or TGF-β receptor 2 (TGFBR2), both of which participate in TGF-β signaling and are risk genes in the GBM process. IGF-1 stimulation promoted both TGFB1 and TGFBR2 expressions. LY2157299, a TGF-β signaling inhibitor, attenuated IGF-1-enhanced GBM cell invasion and mesenchymal transition. By analyzing IGF-1-regulated microRNA (miR) profiles, miR-4286 was found to be significantly downregulated in IGF-1-treated cells and could be targeted to both TGFB1 and TGFBR2. Overexpression of miR-4286 significantly attenuated expressions of the IGF-1-mediated mesenchymal markers, TGFB1 and TGFBR2. Using kinase inhibitors, only U0126 treatment showed an inhibitory effect on IGF-1-reduced miR-4286 and IGF-1-induced TGFB1/TGFBR2 expressions, suggesting that MEK/ERK signaling is involved in the IGF-1/miR-4286/TGF-β signaling axis. Finally, our results suggested that miR-4286 might act as a tumor suppressive microRNA in inhibiting IGF-1-enhanced GBM cell invasion. In conclusion, IGF-1 is connected to TGF-β signaling in regulating the mesenchymal transition and cell invasion of GBM through inhibition of miR-4286. Our findings provide new directions and mechanisms for exploring GBM progression.

胰岛素样生长因子 (IGF)-1 和转化生长因子 (TGF)-β 信号通路都被认为在调节癌症预后中很重要，例如上皮间质转化 (EMT) 和细胞侵袭。然而，多形性胶质母细胞瘤（GBM）中这两种信号通路之间的交叉对话仍不清楚。在本研究中，通过分析来自癌症基因组图谱 (TCGA) 和基因表达综合 (GSE) 4412 的数据，具有较高 IGF-1 水平的 GBM 患者表现出较差的存活率。与 IGF-1 正相关的基因在 EMT 和 TGF-β 信号通路中富集。IGF-1 处理增强了间充质标志物表达和 GBM 细胞侵袭。观察到 IGF-1 与 TGF-β1 (TGFB1) 或 TGF-β 受体 2 (TGFBR2) 显着正相关，两者都参与 TGF-β 信号传导，是 GBM 过程中的风险基因。IGF-1 刺激促进了 TGFB1 和 TGFBR2 的表达。LY2157299 是一种 TGF-β 信号抑制剂，可减弱 IGF-1 增强的 GBM 细胞侵袭和间充质转化。通过分析 IGF-1 调节的 microRNA (miR) 谱，发现 miR-4286 在 IGF-1 处理的细胞中显着下调，并且可以靶向两者TGFB1和TGFBR2。miR-4286 的过表达显着减弱了 IGF-1 介导的间充质标志物 TGFB1 和 TGFBR2 的表达。使用激酶抑制剂，只有 U0126 处理显示出对 IGF-1 降低的 miR-4286 和 IGF-1 诱导的 TGFB1/TGFBR2 表达的抑制作用，表明 MEK/ERK 信号传导参与 IGF-1/miR-4286/TGF -β 信号轴。最后，我们的研究结果表明 miR-4286 可能作为一种抑癌 microRNA 来抑制 IGF-1 增强的 GBM 细胞侵袭。总之，IGF-1 与 TGF-β 信号传导有关，通过抑制 miR-4286 调节 GBM 的间充质转化和细胞侵袭。我们的研究结果为探索 GBM 进展提供了新的方向和机制。