Abstract
We previously identified a pivotal role for G protein α inhibitory subunit 1 (Gαi1) in mediating PI3K-Akt signaling by receptor tyrosine kinases (RTKs). Here, we examined the expression and biological function of Gαi1 in human glioma. Gαi1 mRNA and protein expression were significantly upregulated in human glioma tissues, which correlated with downregulation of an anti-Gαi1 miRNA: microRNA-200a (“miR-200a”). Forced-expression of miR-200a in established (A172/U251MG lines) and primary (patient-derived) human glioma cells resulted in Gαi1 downregulation, Akt inactivation and proliferation inhibition. Reduction of Gαi1 expression by shRNA, dominant negative mutant interference, or complete Gαi1 depletion inhibited Akt activation and cell proliferation. Notably, miR-200a was unable to inhibit glioma cell proliferation when Gαi1 was silenced or mutated. Co-immunoprecipitation studies, in human glioma cells and tissues, show that Gαi1 forms a complex with multiple RTKs (EGFR, PDGFRα, and FGFR) and the adapter protein Gab1. In vivo, the growth of subcutaneous and orthotopic glioma xenografts in nude mice was largely inhibited by expression of Gαi1 shRNA or miRNA-200a. Collectively, miR-200a downregulation in human glioma leads to Gαi1 over-expression, Akt activation and glioma cell proliferation.
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Acknowledgements
This study was supported in part by grants from the National Natural Science Foundation of China (81502162, 81771457, 81371055, and 81570859, 81302195, 31371139 and 81502162, 81571282, 81472786, and 81773192); Grants from Natural Science Foundation of Jiangsu Province (BK20130301, BK20170060, and BK20171248), and by Clinical Special Project of Suzhou (LCZX201601). We thank Dr. John Marshall for English edits and proof-reading of the manuscript.
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Co-first authors: Yuan-yuan Liu, Min-Bin Chen, Long Cheng, Zhi-qing Zhang.
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Liu, Yy., Chen, MB., Cheng, L. et al. microRNA-200a downregulation in human glioma leads to Gαi1 over-expression, Akt activation, and cell proliferation. Oncogene 37, 2890–2902 (2018). https://doi.org/10.1038/s41388-018-0184-5
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DOI: https://doi.org/10.1038/s41388-018-0184-5
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