Blood and lung microRNAs as biomarkers of pulmonary tumorigenesis in cigarette smoke-exposed mice

// Alberto Izzotti 1, 2 , Roumen Balansky 3 , Gancho Ganchev 3 , Marietta Iltcheva 3 , Mariagrazia Longobardi 1 , Alessandra Pulliero 1 , Marta Geretto 1 , Rosanna T. Micale 1 , Sebastiano La Maestra 1 , Mark Steven Miller 4 , Vernon E. Steele 4 , Silvio De Flora 1 1 Department of Health Sciences, University of Genoa, Genoa, Italy 2 IRCCS AOU San Martino IST, Genoa, Italy 3 National Center of Oncology, Sofia, Bulgaria 4 Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA Correspondence to: Silvio De Flora, email: sdf@unige.it Keywords: lung microRNA, blood microRNA, lung carcinogenesis, cigarette smoke, intergender differences Received: July 22, 2016     Accepted: September 22, 2016     Published: October 5, 2016 ABSTRACT Cigarette smoke (CS) is known to dysregulate microRNA expression profiles in the lungs of mice, rats, and humans, thereby modulating several pathways involved in lung carcinogenesis and other CS-related diseases. We designed a study aimed at evaluating ( a ) the expression of 1135 microRNAs in the lung of Swiss H mice exposed to mainstream CS during the first 4 months of life and thereafter kept in filtered air for an additional 3.5 months, ( b ) the relationship between lung microRNA profiles and histopathological alterations in the lung, ( c ) intergender differences in microRNA expression, and ( d ) the comparison with microRNA profiles in blood serum. CS caused multiple histopathological alterations in the lung, which were almost absent in sham-exposed mice. An extensive microRNA dysregulation was detected in the lung of CS-exposed mice. Modulation of microRNA profiles was specifically related to the histopathological picture, no effect being detected in lung fragments with non-neoplastic lung diseases (emphysema or alveolar epithelial hyperplasia), whereas a close association occurred with the presence and multiplicity of preneoplastic lesions (microadenomas) and benign lung tumors (adenomas). Three microRNAs regulating estrogen and HER2-dependent mechanisms were modulated in the lung of adenoma-bearing female mice. Blood microRNAs were also modulated in mice affected by early neoplastic lesions. However, there was a poor association between lung microRNAs and circulating microRNAs, which can be ascribed to an impaired release of mature microRNAs from the damaged lung. Studies in progress are evaluating the feasibility of analyzing blood microRNAs as a molecular tool for lung cancer secondary prevention.