title: miR-494-3p is a novel tumor driver of lung carcinogenesis.
abstract: Lung cancer is the leading cause of tumor-related death worldwide and more efforts are needed to elucidate lung carcinogenesis. Here we investigated the expression of 641 miRNAs in lung tumorigenesis in a K-Ras(+/LSLG12Vgeo);RERTn(ert/ert) mouse model and 113 human tumors. The conserved miRNA cluster on chromosome 12qF1 was significantly and progressively upregulated during murine lung carcinogenesis. In particular, miR-494-3p expression was correlated with lung cancer progression in mice and with worse survival in lung cancer patients. Mechanistically, ectopic expression of miR-494-3p in A549 lung cancer cells boosted the tumor-initiating population, enhanced cancer cell motility, and increased the expression of stem cell-related genes. Importantly, miR-494-3p improved the ability of A549 cells to grow and metastasize in vivo, modulating NOTCH1 and PTEN/PI3K/AKT signaling.Overall, these data identify miR-494-3p as a key factor in lung cancer onset and progression and possible therapeutic target.
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Faversani
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Molecular Pathology Lab. 'PaoLa', Fano, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Amatori
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Augello
authors.affiliation: Flow Cytometry Service, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Colombo
authors.affiliation: Flow Cytometry Service, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Porretti
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Molecular Pathology Lab. 'PaoLa', Fano, Italy.
authors.forename: Mirco
authors.initials: M
authors.lastname: Fanelli
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrero
authors.affiliation: Division of Thoracic Surgery and Lung Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Palleschi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy.
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Belloni
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ercoli
authors.affiliation: Biology Department, Nerviano Medical Sciences s.r.l., Nerviano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Degrassi
authors.affiliation: Laboratory of Medical Genetics, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Baccarin
authors.affiliation: Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vaira
authors.affiliation: Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.|Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D011905:Genes, ras; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D058985:Side-Population Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: C547168:MIRN494 microRNA, human; D035683:MicroRNAs; C550178:Mirn494 microRNA, mouse; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: NOTCH1; NSCLC; miR-494-3p; miRNA; stem cells