title: mir-660-p53-mir-486 Network: A New Key Regulatory Pathway in Lung Tumorigenesis.
abstract: Lung cancer is the most frequent cause of cancer-related death worldwide, with limited therapeutic options and rapid development of drug resistance. MicroRNAs, a class of small non-coding RNAs that control different physiological processes, have been associated with cancer development, as either oncomiRNAs or tumor-suppressor miRNAs. In the present study we investigated the interaction between mir-486-5p and mir-660-5p, two independent tumor-suppressor miRNAs, to assess their possible role and synergistic effect in lung cancer treatment. Our data show that mir-660-5p over-expression in A549 lung cancer cells induced a remarkable increase in mir-486-5p expression level and activity, detected as a reduction of its target gene, p85. mir-486-5p expression was confirmed by microRNA in situ hybridization. mir-660-5p modulated mir-486-5p through the silencing of Mouse Double Minute 2 (MDM2), one of its direct target, and then through p53 stimulation. This regulatory pathway was effective in A549, but not in H1299; therefore, only in the context of a functional p53 protein. Our findings support the conclusion that mir-486-5p is positively regulated by mir-660-5p in lung cancer cell lines, through the mir-660-MDM2-p53 pathway, making mir-660-5p even more interesting for its potential successful use in lung cancer therapy.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Tumor Genomics, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. cristina.borzi@istitutotumori.mi.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Borzi
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Tumor Genomics, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. linda.calzolari@istitutotumori.mi.it.
authors.forename: Linda
authors.initials: L
authors.lastname: Calzolari
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Tumor Genomics, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. giovanni.centonze@istitutotumori.mi.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Centonze
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. massimo.milione@istitutotumori.mi.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Milione
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Tumor Genomics, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. gabriella.sozzi@istitutotumori.mi.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Tumor Genomics, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. orazio.fortunato@istitutotumori.mi.it.
authors.forename: Orazio
authors.initials: O
authors.lastname: Fortunato
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C560945:MIRN486 microRNA, human; C577172:MIRN660 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: lung cancer; miRNAs; p53