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.
Highlights
Exposure to cigarette smoke (CS) has been shown to extensively dysregulate the expression of microRNAs, mostly in the sense of downregulation, in pulmonary cells of mice [1], rats [2], and humans [3]
The results show that none of the sham-exposed mice had histopathological lesions, with the exception of one female that developed 3 microadenomas detectable in the whole lungs
The results of histopathological analyses confirmed that exposure of mice to mainstream CS (MCS) during the first 4 months of life, followed by 3-4 months in filtered air in order to allow a better growth of pulmonary lesions, results in the appearance of significant alterations and especially of alveolar epithelial hyperplasias, microadenomas, and adenomas
Summary
Exposure to cigarette smoke (CS) has been shown to extensively dysregulate the expression of microRNAs (miRNAs), mostly in the sense of downregulation, in pulmonary cells of mice [1], rats [2], and humans [3]. The first one was to comparatively evaluate miRNA expression profile in samples from sham-exposed mice and mice that had been exposed to MCS during the first 4 months of life and thereafter kept in filtered air for an additional 3.5 months This carcinogenesis model has been developed in our laboratories [7] and applied to investigate both efficacy and safety of a number of dietary and pharmacological agents in CS-related carcinogenesis [8]. This allowed us to evaluate pulmonary miRNA expression profiles as related to the occurrence of non-neoplastic lesions (lung emphysema), preneoplastic lesions (hyperplasia of the alveolar epithelium and microadenomas) and benign tumors (adenomas) In this way, it was possible to assess both sensitivity and specificity of miRNA analysis in characterizing these lesions. By comparing miRNA profiles in the lung and blood serum of all mice, we aimed at validating the detection of circulating miRNAs as a secondary prevention tool to be used in translational studies and in possible applications in humans
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