title: Relationships between pulmonary micro-RNA and proteome profiles, systemic cytogenetic damage and lung tumors in cigarette smoke-exposed mice treated with chemopreventive agents.
abstract: Assessing the correlation between molecular endpoints and cancer induction or prevention aims at validating the use of intermediate biomarkers. We previously developed murine models that are suitable to detect both the carcinogenicity of mainstream cigarette smoke (MCS) and the induction of molecular alterations. In this study, we used 931 Swiss mice in two parallel experiments and in a preliminary toxicity study. The chemopreventive agents included vorinostat, myo-inositol, bexarotene, pioglitazone and a combination of bexarotene and pioglitazone. Pulmonary micro-RNAs and proteins were evaluated by microarray analyses at 10 weeks of age in male and female mice, either unexposed or exposed to MCS since birth, and either untreated or receiving each one of the five chemopreventive regimens with the diet after weaning. At 4 months of age, the frequency of micronucleated normochromatic erythrocytes was evaluated. At 7 months, the lungs were subjected to standard histopathological analysis. The results showed that exposure to MCS significantly downregulated the expression of 79 of 694 lung micro-RNAs (11.4%) and upregulated 66 of 1164 proteins (5.7%). Administration of chemopreventive agents modulated the baseline micro-RNA and proteome profiles and reversed several MCS-induced alterations, with some intergender differences. The stronger protective effects were produced by the combination of bexarotene and pioglitazone, which also inhibited the MCS-induced clastogenic damage and the yield of malignant tumors. Pioglitazone alone increased the yield of lung adenomas. Thus, micro-RNAs, proteins, cytogenetic damage and lung tumors were closely related. The molecular biomarkers contributed to evaluate both protective and adverse effects of chemopreventive agents and highlighted the mechanisms involved.
authors.affiliation: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Izzotti
authors.forename: Roumen
authors.initials: R
authors.lastname: Balansky
authors.forename: Francesco
authors.initials: F
authors.lastname: D'Agostini
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Longobardi
authors.forename: Cristina
authors.initials: C
authors.lastname: Cartiglia
authors.forename: Sebastiano
authors.initials: S
authors.lastname: La Maestra
authors.forename: Rosanna T
authors.initials: RT
authors.lastname: Micale
authors.forename: Anna
authors.initials: A
authors.lastname: Camoirano
authors.forename: Gancho
authors.initials: G
authors.lastname: Ganchev
authors.forename: Marietta
authors.initials: M
authors.lastname: Iltcheva
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: Silvio
authors.initials: S
authors.lastname: De Flora
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000401:mortality; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D020543:Proteome; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*
chemical_list: D016588:Anticarcinogenic Agents; D035683:MicroRNAs; D020543:Proteome; D012906:Smoke