Ionizing radiation-inducible miR-494 promotes glioma cell invasion through EGFR stabilization by targeting p190B RhoGAP

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• 作者：Seo-Young Kwak ; Ji-Sook Yang ; Bu-Yeon Kim ; In Hwa Bae ; Young-Hoon Han
• 关键词：ECM ; extracellular matrix ; EGF ; epidermal growth factor ; EGFR ; epidermal growth factor receptor (EGFR) ; FACS ; fluorescence-activated cell sorting ; FBS ; fetal bovine serum ; GAP ; GTPase activating protein ; GEF ; guanine nucleotide exchange factor ; IR ; ionizing radiation ; LNA ; locked nucleic acid ; MAPK ; mitogen activated protein kinase ; miRNA ; microRNA ; MMP ; metalloproteinase ; NLK ; Nemo-like kinase ; ORF ; open reading frame ; PAGE ; polyacrylamide gel electrophoresis ; PI3K ; phosphatidylinositol 3-kinas
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：March, 2014
• 年：2014
• 卷：1843
• 期：3
• 页码：508-516
• 全文大小：1626 K

文摘

MicroRNAs (miRNAs) play an important role in various stages of tumor progression. miR-494, which we had previously identified as a miRNA induced by ionizing radiation (IR) in the glioma cell line U-251, was observed to enhance invasion of U-251 cells by activating MMP-2. The miR-494-induced invasive potential was accompanied by, and dependent on, epidermal growth factor receptor (EGFR) upregulation and the activation of its downstream signaling constituents, Akt and ERK. The upregulation of EGFR by miR-494 involved the suppression of lysosomal protein turnover. Among the putative target proteins tested, p190B RhoGAP (p190B) was downregulated by miR-494, and its reduced expression was responsible for the increase in EGFR expression. A reporter assay using a luciferase construct containing p190B 3鈥?untranslated region (3鈥睻TR) confirmed that p190B is a direct target of miR-494. Downregulation of p190B by small interfering RNA (siRNA) transfection closely mimicked the outcomes of miR-494 transfection, and showed increased EGFR expression, MMP-2 secretion, and invasion. Ectopic expression of p190B suppressed the miR-494-induced EGFR upregulation and invasion promotion, thereby suggesting that p190B depletion is critical for the invasion-promoting action of miR-494. Collectively, our results suggest a novel function for miR-494 and its potential application as a target to control invasiveness in cancer therapy.