miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma.

Abstract

Glioblastoma multiforme (GBM) and the mesenchymal GBM subtype in particular are highly malignant tumors that frequently exhibit regions of severe hypoxia and necrosis. Because these features correlate with poor prognosis, we investigated microRNAs whose expression might regulate hypoxic GBM cell survival and growth. We determined that the expression of microRNA-218 (miR-218) is decreased significantly in highly necrotic mesenchymal GBM, and orthotopic tumor studies revealed that reduced miR-218 levels confer GBM resistance to chemotherapy. Importantly, miR-218 targets multiple components of receptor tyrosine kinase (RTK) signaling pathways, and miR-218 repression increases the abundance and activity of multiple RTK effectors. This elevated RTK signaling also promotes the activation of hypoxia-inducible factor (HIF), most notably HIF2α. We further show that RTK-mediated HIF2α regulation is JNK dependent, via jun proto-oncogene. Collectively, our results identify an miR-218-RTK-HIF2α signaling axis that promotes GBM cell survival and tumor angiogenesis, particularly in necrotic mesenchymal tumors.

DOI: 10.1073/pnas.1314341111
01002002014201520162017
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@article{Mathew2014miR218OA, title={miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma.}, author={Lijoy K Mathew and Nicolas Skuli and Vera Mucaj and Samuel S Lee and Pascal O Zinn and Pratheesh Sathyan and Hongxia Z Imtiyaz and Zhongfa Zhang and Ramana V Davuluri and Shilpa Rao and Sriram Venneti and Priti Lal and Justin D Lathia and Jeremy N Rich and Brian Keith and Andy J Minn and M Celeste Simon}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2014}, volume={111 1}, pages={291-6} }