Abstract
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.
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The data that support the findings of this study are available from the corresponding author, Ku-Chung Chen, upon reasonable request.
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Acknowledgements
This study was sponsored by the Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (2018SKHADR030 to Chin-Cheng Lee); the Ministry of Science and Technology, Taiwan (Contract Grant No. MOST 106-2320-B-038-051-MY3 to Ku-Chung Chen and MOST 108-2314-B-038-110 to Chwen-Ming Shih); Taipei City Government (Contract Grant No. 10801-62-082 to Ann-Jeng Liu); Taipei City Hospital Ren-Ai Branch (Contract Grant No. TPCH-109-10 to Ann-Jeng Liu); and Taipei Medical University-Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (intramural grant no. SKH-TMU-107-03 to Ku-Chung Chen). We thank the National RNAi Core Facility at Academia Sinica, Taiwan for providing shRNA reagents and related services. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding
This study was sponsored by the Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (2018SKHADR030 to Chin-Cheng Lee); the Ministry of Science and Technology, Taiwan (Contract Grant No. MOST 106-2320-B-038-051-MY3 to Ku-Chung Chen and MOST 108-2314-B-038-110 to Chwen-Ming Shih); Taipei City Government (Contract Grant No. 10801-62-082 to Ann-Jeng Liu); Taipei City Hospital Ren-Ai Branch (Contract Grant No. TPCH-109-10 to Ann-Jeng Liu); and Taipei Medical University-Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (Intramural Grant No. SKH-TMU-107-03 to Ku-Chung Chen).
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KH, CL, and KC conceived of the presented idea. KH, PC, and YL carried out the experiment. KH and PC wrote the manuscript. CS, CC, and AL verified the analytical methods. CL and KC supervised the findings of this work and contributed to the final version of the manuscript. All authors discussed the results, provided critical feedback, and helped shape the research, analysis and manuscript.
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Ho, KH., Chen, PH., Shih, CM. et al. miR-4286 is Involved in Connections Between IGF-1 and TGF-β Signaling for the Mesenchymal Transition and Invasion by Glioblastomas. Cell Mol Neurobiol 42, 791–806 (2022). https://doi.org/10.1007/s10571-020-00977-1
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DOI: https://doi.org/10.1007/s10571-020-00977-1