Carcinogenesis Advance Access originally published online on September 9, 2008
Carcinogenesis 2008 29(12):2394-2399; doi:10.1093/carcin/bgn209
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Differential expression of microRNAs in early-stage neoplastic transformation in the lungs of F344 rats chronically treated with the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
1 Department of Pharmacology
2 Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
* To whom correspondence should be addressed. Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street Southeast, Minneapolis, MN 55455, USA. Tel: +1 612 625 4479; Fax: +1 612 625 8408; Email: zengx033{at}umn.edu
While numerous microRNAs (miRNAs) have been reported to alter their expression levels in human lung cancer tissues compared with normal tissues, the function of these miRNAs and their contribution to the long process of lung cancer development remains largely unknown. We applied a tobacco-specific carcinogen-induced cancer model to investigate the involvement of miRNAs in early lung cancer development, which could also provide information on potential, early biomarkers of lung cancers. Male F344 rats were first chronically treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogen present in tobacco products, for up to 20 weeks. The expression profiles of miRNAs in rat lungs were then determined. As measured by miRNA microarrays and confirmed by Northern blot and real-time polymerase chain reaction analyses, NNK treatment reduced the expression of a number of miRNAs, such as miR-101, miR-126*, miR-199 and miR-34. Significantly, these miRNAs overlap with previously published reports on altered miRNA expression in human lung cancer samples. These miRNAs might, therefore, represent early-response miRNAs that signify the molecular changes associated with pulmonary tumorigenesis. Moreover, we identified cytochrome P450 (CYP) 2A3, a critical enzyme in rat lungs that activates NNK to render it carcinogenic, as a potential target of miR-126*. NNK treatment in rats repressed miR-126* but induced CYP2A3 expression, a mechanism that may potentiate the oncogenic effects of NNK.
Abbreviations: CYP, cytochrome P450; miRNA, microRNA; mRNA, messenger RNA; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; PCR, polymerase chain reaction; snRNA, small nuclear RNA; UTR, untranslated region
Received June 10, 2008; revised August 25, 2008; accepted September 1, 2008.
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