title: MicroRNA-1826 directly targets beta-catenin (CTNNB1) and MEK1 (MAP2K1) in VHL-inactivated renal cancer.
abstract: The aim of this project is to identify new therapeutic microRNAs (miRNAs) for von Hippel-Lindau (VHL)-inactivated renal cancer cells. We initially identified several potential miRNAs targeting CTNNB1 and MEK1 using several targets scan algorithms. Only miR-1826 was found to target CTNNB1 and MEK1. Therefore, we focused on miRNA-1826 and performed 3' untranslated region (UTR) luciferase assay, functional analyses and association study between miR-1826 expression and renal cancer patient outcomes. miR-1826 expression was significantly lower in renal cancer tissues compared with non-neoplastic areas and lower expression was significantly associated with overall shorter survival and earlier recurrence after radical nephrectomy. Following miR-1826 transfection, 3' UTR luciferase activity and protein expression of beta-catenin and MEK1 were significantly downregulated in renal cancer cells. Introduction of miR-1826 also inhibited renal cancer cell proliferation, invasion and migration. Additionally, miR-1826 promoted apoptosis and G(1) arrest in VHL-inactivated renal cancer cells. Knockdowns of CTNNB1 and MEK1 by small interfering RNAs reproduced the tumor-suppressive effect of miR-1826. Our data suggest that the miR-1826 plays an important role as a tumor suppressor by downregulating beta-catenin and MEK1 in VHL-inactivated renal cancers.
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA 94121, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirata
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hinoda
authors.forename: Koji
authors.initials: K
authors.lastname: Ueno
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakajima
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Ishii
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D056726:Genetic Association Studies; D006801:Humans; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D034741:RNA, Small Interfering; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C570042:MIRN1826 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D051176:beta Catenin; D008156:Luciferases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human