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

• Published in: Cell death and differentiation 2014-05, Vol.21 (5), p.720-734
• Main Authors: Zhang, Y, Kim, J, Mueller, A C, Dey, B, Yang, Y, Lee, D-h, Hachmann, J, Finderle, S, Park, D M, Christensen, J, Schiff, D, Purow, B, Dutta, A, Abounader, R
• Format: Article
• Language: English
• Subjects: 631/337/384/331; 631/67/1922; 631/80/86; Animals; Apoptosis; Apoptosis - physiology; Biochemistry; Biomedical and Life Sciences; Brain cancer; Brain Neoplasms - enzymology; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Cancer therapies; Cell Biology; Cell Cycle Analysis; Cell death; Cell Growth Processes - physiology; Cell Line, Tumor; Crizotinib; Glioblastoma - enzymology; Glioblastoma - genetics; Glioblastoma - pathology; Humans; Immunology; Kinases; Life Sciences; Medical prognosis; Mice; MicroRNAs; MicroRNAs - biosynthesis; MicroRNAs - genetics; MicroRNAs - metabolism; Original Paper; Physiology; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins p21(ras); Pyrazoles - pharmacology; Pyridines - pharmacology; ras Proteins - genetics; ras Proteins - metabolism; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Signal transduction; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Stem Cells; Transfection; Tumors
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2013.196

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.