Abstract
Glioma is one of the most common malignancies of the central nervous system. The therapeutic effect has not been satisfactory despite advances in comprehensive treatment techniques. Our previous studies have found that triptolide inhibits glioma proliferation through the ROS/JNK pathway, but in-depth mechanisms need to be explored. Recent studies have confirmed that miRNAs may function as tumor suppressor genes or oncogenes and be involved in cancer development and progression. In this study, we found that let-7b-5p expression levels closely correlated with WHO grades and overall survival in patients in tumor glioma-CGGA-mRNAseq-325, and the upregulation of let-7b-5p can inhibit the proliferation and induce apoptosis of glioma cells. Functionally, upregulation of let-7b-5p increased the inhibitory effect on cell viability and colony formation caused by triptolide and promoted the apoptosis rate of triptolide-treated U251 cells. Conversely, downregulation of let-7b-5p had the opposite effect, indicating that let-7b-5p is a tumor suppressor miRNA in glioma cells. Moreover, target prediction, luciferase reporter assays and functional experiments revealed that IGF1R was a direct target of let-7b-5p. In addition, upregulation of IGF1R reversed the triptolide-regulated inhibition of cell viability but promoted glioma cell apoptosis and activated the ROS/JNK signaling pathway induced by triptolide. The results obtained in vivo experiments substantiated those from the in vitro experiments. In summary, the current study provides evidence that triptolide inhibits the growth of glioma cells by regulating the let-7b-5p-IGF1R-ROS/JNK axis in vitro and in vivo. These findings may provide new ideas and potential targets for molecularly targeted therapies for comprehensive glioma treatment.
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The data used to support the findings of this study are available from the corresponding author upon request.
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Funding
This work was supported by the National Natural Science Foundation of China (82004108, 82104579), Training Program for Young Backbone Teachers of Higher Education Institutions in Henan Province (2023GGJS082), Henan Provincial Science and Technology Research Project (202102310180) and Natural Science Foundation of Henan Province (202300410258).
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Xihong Liu, Liping Yang, and Yulong Chen conceived and designed the research. Xihong Liu, Peiyuan Zhao, and Xiaodan Du conducted experiments. Xihong Liu and Peiyuan Zhao wrote the manuscript. Junlin Hou, Guanghui Zhang, and Wenxian Zhang participated in data collection and analysis. The authors declare that all data were generated in-house and that no paper mill was used.
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Liu, X., Zhao, P., Du, X. et al. Let-7b-5p promotes triptolide-induced growth-inhibiting effects in glioma by targeting IGF1R. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-02957-4
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DOI: https://doi.org/10.1007/s00210-024-02957-4