title: MiR-181a-5p is downregulated in hepatocellular carcinoma and suppresses motility, invasion and branching-morphogenesis by directly targeting c-Met.
abstract: c-Met receptor tyrosine kinase has been regarded as a promising therapeutic target for hepatocellular carcinoma (HCC). Recently, microRNAs (miRNAs) have been shown as a novel mechanism to control c-Met expression in cancer. In this study, we investigate the potential contribution of miR-181a-5p dysregulation to the biology of c-Met overexpression in HCC. Herein, we found an inverse expression pattern between miR-181a-5p and c-Met expression in normal, cirrhotic and HCC liver tissues. Luciferase assay confirmed that miR-181a-5p binding to the 3'-UTR of c-Met downregulated the expression of c-Met in HCC cells. Overexpression of miR-181a-5p suppressed both HGF-independent and -dependent activation of c-Met and consequently diminished branching-morphogenesis and invasion. Combined treatment with miR-181a-5p and c-Met inhibitor led to a further inhibition of c-Met-driven cellular activities. Knockdown of miR-181a-5p promoted HGF-independent/-dependent signaling of c-Met and accelerated migration, invasion and branching-morphogenesis. In conclusion, our results demonstrated for the first time that c-Met is a functional target gene of miR-181a-5p and the loss of miR-181a-5p expression led to the activation of c-Met-mediated oncogenic signaling in hepatocarcinogenesis. These findings display a novel molecular mechanism of c-Met regulation in HCC and strategies to increase miR-181a5p level might be an alternative approach for the enhancement of the inhibitory effects of c-Met inhibitors.
authors: Department of Medical Biology, Dokuz Eylul University Medical School, Inciralti, 35340 Izmir, Turkey.
authors: Peyda
authors: P
authors: Korhan
authors: Department of Medical Biology, Dokuz Eylul University Medical School, Inciralti, 35340 Izmir, Turkey.
authors: Esra
authors: E
authors: Erdal
authors: Department of Medical Biology, Dokuz Eylul University Medical School, Inciralti, 35340 Izmir, Turkey. Electronic address: nese.atabey@deu.edu.tr.
authors: Neşe
authors: N
authors: Atabey
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D035683:MicroRNAs; D009024:Morphogenesis; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
keywords: Branching-morphogenesis; Hepatocellular carcinoma; Motility/invasion; c-Met; miR-181a-5p