Priority Research Papers:
miR-494-3p is a novel tumor driver of lung carcinogenesis
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Alice Faversani1, Stefano Amatori2, Claudia Augello1,3, Federico Colombo4, Laura Porretti4, Mirco Fanelli2, Stefano Ferrero1,5, Alessandro Palleschi6, Pier Giuseppe Pelicci7,8, Elena Belloni7, Giulia Ercoli1, Anna Degrassi9, Marco Baccarin10, Dario C. Altieri11, Valentina Vaira1,3,* and Silvano Bosari1,3,*
1 Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico , Milan, Italy
2 Department of Biomolecular Sciences, University of Urbino ‘Carlo Bo’, Molecular Pathology Lab. ‘PaoLa’, Fano, Italy
3 Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
4 Flow Cytometry Service, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
5 Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
6 Division of Thoracic Surgery and Lung Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
7 Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
8 Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
9 Biology Department, Nerviano Medical Sciences s.r.l., Nerviano, Italy
10 Laboratory of Medical Genetics, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
11 Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America
* These Authors have contributed equally to the study
Valentina Vaira, email:
Silvano Bosari, email:
Keywords: miR-494-3p, miRNA, NSCLC, NOTCH1, stem cells
Received: August 05, 2016 Accepted: December 07, 2016 Published: December 14, 2016
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.
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