Research ArticleCancer

Feedback circuitry between miR-218 repression and RTK activation in glioblastoma

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Sci. Signal.  05 May 2015:
Vol. 8, Issue 375, pp. ra42
DOI: 10.1126/scisignal.2005978

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Loss of the micromanager in glioblastoma

Increased signaling by receptor tyrosine kinases (RTKs) promotes cell proliferation in many cancers. Glioblastoma frequently exhibits loss of miR-218, a microRNA that inhibits the production of various RTKs, including epidermal growth factor receptor (EGFR). Mathew et al. found that EGF stimulated the activity of STAT3, which recruited a protein that inhibited the transcription of miR-218 in glioblastoma cells. Glioblastoma cells with reduced abundance of miR-218 had increased abundance of multiple RTKs (EGFR included) and downstream pathway components, which promoted the proliferation of the cells in culture and the growth of tumors when injected into mouse brains. Thus, increased EGFR signaling and decreased miR-218 expression produced an oncogenic feedback loop that contributes to the growth of glioblastoma.

Abstract

Receptor tyrosine kinase (RTK) signaling promotes the growth and progression of glioblastoma (GBM), a highly aggressive type of brain tumor. We previously reported that decreased miR-218 expression in GBM directly promotes RTK activity by increasing the expression of key RTKs and their signaling mediators, including the RTK epidermal growth factor receptor (EGFR), phospholipase C–γ1 (PLCγ1), and the kinases PIK3CA and ARAF. However, increased RTK signaling usually activates negative feedback mechanisms to maintain homeostasis. We found that decreased miR-218 expression in GBM cells also increased the expression of genes encoding additional upstream and downstream components of RTK signaling pathways, including the RTK platelet-derived growth factor receptor α (PDGFRα) and the kinases ribosomal S6 kinase 2 (RSK2) and S6 kinase 1 (S6K1), that collectively overrode the negative feedback mechanism. Furthermore, increased RTK signaling itself suppressed miR-218 expression. Mass spectrometry and DNA pull-down identified binding of signal transducer and activator of transcription 3 (STAT3) along with the transcriptional repressor BCL2-associated transcription factor 1 (BCLAF1) directly to the miR-218 locus. These data identify previously unknown feedback loops by which miR-218 repression promotes increased RTK signaling in high-grade gliomas.

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