Analysis of miRNA profiles identified miR-196a as a crucial mediator of aberrant PI3K/AKT signaling in lung cancer cells
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Ilaria Guerriero1, Daniela D’Angelo2, Pierlorenzo Pallante2, Mafalda Santos1, Marianna Scrima1, Donatella Malanga3, Carmela De Marco3,Maria Ravo4, Alessandro Weisz4, Carmelo Laudanna3, Michele Ceccarelli1, 5, Geppino Falco1, 6, Antonia Rizzuto7, Giuseppe Viglietto1, 3
1Biogems.c.ar.l., Istituto di Ricerche Genetiche “Gaetano Salvatore”, Ariano Irpino, Avellino, Italy
2Istituto per l’Endocrinologia e l’Oncologia Sperimentale, IEOS-CNR, c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università “Federico II” of Napoli, Napoli, Italy
3Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia of Catanzaro, Italy
4Laboratorio di Medicina Molecolare e Genomica, Dipartimentodi Medicina e Chirurgia, Università di Salerno, Baronissi, Italy
5Department of Biological and Environmental Studies, Università del Sannio, Benevento, Italy
6Dipartimento di Biologia, Università degli Studi di Napoli Federico II, Complesso Universitario Monte S.Angelo, Napoli, Italy
7Dipartimento di Scienze Mediche e Chirurgiche, Università Magna Graecia of Catanzaro, Italy
Giuseppe Viglietto, email: [email protected]
Keywords: NSCLC, PI3K/AKT, microRNA, miR-196a
Received: January 11, 2016 Accepted: November 02, 2016 Published: November 17, 2016
Hyperactivation of the PI3K/AKT pathway is observed in most human cancer including lung carcinomas. Here we have investigated the role of miRNAs as downstream targets of activated PI3K/AKT signaling in Non Small Cell Lung Cancer (NSCLC). To this aim, miRNA profiling was performed in human lung epithelial cells (BEAS-2B) expressing active AKT1 (BEAS-AKT1-E17K), active PI3KCA (BEAS-PIK3CA-E545K) or with silenced PTEN (BEAS-shPTEN).
Twenty-four differentially expressed miRNAs common to BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells were identified through this analysis, with miR-196a being the most consistently up-regulated miRNA. Interestingly, miR-196a was significantly overexpressed also in human NSCLC-derived cell lines (n=11) and primary lung cancer samples (n=28).
By manipulating the expression of miR-196a in BEAS-2B and NCI-H460 cells, we obtained compelling evidence that this miRNA acts downstream the PI3K/AKT pathway, mediating some of the proliferative, pro-migratory and tumorigenic activity that this pathway exerts in lung epithelial cells, possibly through the regulation of FoxO1, CDKN1B (hereafter p27) and HOXA9.
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