Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

Abstract

Receptor tyrosine kinases (RTKs) are co-deregulated in a majority of glioblastoma (GBM), the most common and most deadly brain tumor. We show that the RTKs MET, EGFR, and PDGFR regulate microRNA-134 (miR-134) in GBM. We find that miR-134 is downregulated in human tumors and cancer stem cells and that its expression inversely correlates with the activation of MET, EGFR, and PDGFR. We demonstrate that miR-134 inhibits cancer cell and stem-cell proliferation, survival, and xenograft growth, as well as cancer stem-cell self-renewal and stemness. We identify KRAS and STAT5B as targets of miR-134, and establish molecular and functional links between RTKs, miR-134, KRAS/STAT5B and malignancy in vitro and in vivo. We show that miR-134 induction is required for the anti-tumor effects of RTK inhibitors. We also uncover the molecular pathways through which RTKs regulate miR-134 expression and demonstrate the involvement of MAPK signaling and the KLF4 transcription factor. We therefore identify miR-134 as a novel RTK-regulated tumor-suppressive hub that mediates RTK and RTK-inhibitor effects on GBM malignancy by controlling KRAS and STAT5B. Cell Death and Differentiation (2014) 21, 720-734; doi:10.1038/cdd.2013; published online 17 January 2014 microRNAs (miRNAs) regulate a wide variety of physiological and pathological processes. 1-3 miRNAs modulate protein expression by binding to the 3 0 untranslated region (3 0 UTR) of target mRNA and promoting RNA degradation and/or inhibiting translation. Single miRNAs can regulate multiple molecules, highlighting a powerful mechanism for the regulation of redundant and cross-talking signal transduction pathways. 4 miRNA dysregulation is a common feature of neoplasia and numerous miRNAs have been characterized as oncogenes or tumor suppressors in many cancers including in glioblastoma (GBM). 3,[5][6][7][8][9][10][11] microRNA-134 (miR-134) has been implicated in the regulation of physiological and developmental processes. It was shown to promote mouse embryonic stem-cell differentiation, dendritogenesis, and stage-specific cortical development. 12-17 miR-134 is downregulated by SIRT1 and involved in synaptic plasticity and memory formation. 18 miR-134 expression is regulated by MEF2 in dendritogenesis 14 and GBM. 19 GBM is the most common and most deadly primary malignant brain tumor. 20,21 The Cancer Genome Atlas and other studies have shown that aberrant expression or activation of the receptor tyrosine kinases (RTKs) EGFR, MET, and PDGFR occurs in a majority of GBM and correlates with poor prognosis. 22 Importantly, multiple RTKs are co-activated in the same GBM tumors and tumor cells. 23,24 KRAS, STAT3, and STAT5 are activated by RTKs and mediate their oncogenic effects. [25][26][27][28] The failure of current treatments for GBM is arguably due to the presence in the tumors of GBM stem cells (GSCs) that are resistant to radioand chemo-therapy and capable of maintaining and propagating the tumors. 29-31 EGFR, MET, PDGFR, and miRNAs have been implicated in the regulation of GSC f...

MicroRNA-134 modulates glioma cell U251 proliferation and invasion by targeting KRAS and suppressing the ERK pathway

“…And it was reported that Kirsten rat sarcoma viral oncogene homolog (Kras), signal transducer and activator of transcription 3 (STAT3), and STAT5 were activated by the RTKs and involved in the process of oncogenesis [28][29][30]. Of note, it was KRAS that was targeted directly by miR-134, and their interaction played a protective role in restraining proliferation of renal carcinoma cells and blocking progression of glioblastoma [31][32][33]. Furthermore, extracellular signal-regulated kinase (ERK) signaling appeared as critical effectors of KRAS, and KRAS has also been reported to induce feedback signals that regulated activation of ERK, an oncogene frequently confirmed to modify glioma development [34][35][36][37].…”

MicroRNA-134 reverses multidrug resistance in human lung adenocarcinoma cells by targeting FOXM1

“…The downregulation of miR-134 is a frequent occurrence in various types of cancer, suggesting that miR-134 may be important in tumorigenesis and tumor progression (18)(19)(20). Sun et al (18) indicated that miR-134 served a pivotal role in non-small cell lung cancer through inhibiting cell proliferation, migration and invasion, and promoting apoptosis by targeting the oncogenic cyclin D1 gene.…”

Deregulated microRNA expression in biospecimens from patients diagnosed with schizophrenia and bipolar disorder as a disease biomarker

“…Further, miR-134 plasma levels were significantly different between BD patients (medicated as well as drugfree) and controls [51]. miR-134 differential expression in SZ and BD further extends the list of brain diseases in which miR-134 seems to be deregulated: human anencephaly [52], glioblastoma [53,54], cognitive impairment [55], and epilepsy [56]. These wide-ranging implications of miR-134 in brain pathologies likely stem from its documented roles in cortical neuronal development [57], nerve growth cone guidance [58], dendritogenesis [59,60], learning, memory and plasticity [61,62].…”