Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):291-6. doi: 10.1073/pnas.1314341111. Epub 2013 Dec 24.

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

Author information

1
Abramson Family Cancer Research Institute, Howard Hughes Medical Institute, Penn Molecular Profiling Facility - Bioinformatics Group, and Departments of Cell and Developmental Biology, Pathology and Laboratory Medicine, Cancer Biology, and Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104.

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.

PMID:
24368849
PMCID:
PMC3890843
DOI:
10.1073/pnas.1314341111
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center