title: MicroRNA-148a reduces tumorigenesis and increases TRAIL-induced apoptosis in NSCLC.
abstract: Nonsmall cell lung cancer (NSCLC) is one of the leading causes of death worldwide. TNF-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells without inducing significant toxicity in normal cells. However, several carcinomas, including lung cancer, remain resistant to TRAIL. MicroRNAs (miRNAs) are small noncoding RNAs of ∼ 24 nt that block mRNA translation and/or negatively regulate its stability. They are often aberrantly expressed in cancer and have been implicated in increasing susceptibility or resistance to TRAIL-induced apoptosis by inhibiting key functional proteins. Here we show that miR-148a is down-regulated in cells with acquired TRAIL-resistance compared with TRAIL-sensitive cells. Enforced expression of miR-148a sensitized cells to TRAIL and reduced lung tumorigenesis in vitro and in vivo through the down-modulation of matrix metalloproteinase 15 (MMP15) and Rho-associated kinase 1 (ROCK1). These findings suggest that miR-148a acts as a tumor suppressor and might have therapeutic application in the treatment of NSCLC.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;
authors.forename: Pooja
authors.initials: P
authors.lastname: Joshi
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Laganà
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;
authors.forename: Justin
authors.initials: J
authors.lastname: Middleton
authors.affiliation: Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, 44100 Ferrara, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.affiliation: Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, United Kingdom michela.garofalo@cruk.manchester.ac.uk carlo.croce@osumc.edu.
authors.forename: Michela
authors.initials: M
authors.lastname: Garofalo
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210; michela.garofalo@cruk.manchester.ac.uk carlo.croce@osumc.edu.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D063646:Carcinogenesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
chemical_list: C550570:MIRN148 microRNA, human; D035683:MicroRNAs; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human
keywords: chemoresistance; lung cancer; microRNA