MiR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

Lijoy K. Mathew, Nicolas Skuli, Vera Mucaj, Samuel S. Lee, Pascal O. Zinn, Pratheesh Sathyan, Hongxia Z. Imtiyaz, Zhongfa Zhang, Ramana V. Davuluri, Shilpa Rao, Sriram Venneti, Priti Lal, Justin D. Lathia, Jeremy N. Rich, Brian Keith, Andy J. Minn, M. Celeste Simon*

*Corresponding author for this work

Research output: Contribution to journalArticle

70 Scopus citations

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 micro- RNAs 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.

Original languageEnglish (US)
Pages (from-to)291-296
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number1
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • General

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    Mathew, L. K., Skuli, N., Mucaj, V., Lee, S. S., Zinn, P. O., Sathyan, P., Imtiyaz, H. Z., Zhang, Z., Davuluri, R. V., Rao, S., Venneti, S., Lal, P., Lathia, J. D., Rich, J. N., Keith, B., Minn, A. J., & Simon, M. C. (2014). MiR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma. Proceedings of the National Academy of Sciences of the United States of America, 111(1), 291-296. https://doi.org/10.1073/pnas.1314341111