Chemoprevention of Cigarette Smoke-Induced Alterations of MicroRNA Expression in Rat Lungs
ABSTRACT We previously showed that exposure to environmental cigarette smoke (ECS) for 28 days causes extensive downregulation of microRNA expression in the lungs of rats, resulting in the overexpression of multiple genes and proteins. In the present study, we evaluated by microarray the expression of 484 microRNAs in the lungs of either ECS-free or ECS-exposed rats treated with the orally administered chemopreventive agents N-acetylcysteine, oltipraz, indole-3-carbinol, 5,6-benzoflavone, and phenethyl isothiocyanate (as single agents or in combinations). This is the first study of microRNA modulation by chemopreventive agents in nonmalignant tissues. Scatterplot, hierarchical cluster, and principal component analyses of microarray and quantitative PCR data showed that none of the above chemopreventive regimens appreciably affected the baseline microRNA expression, indicating potential safety. On the other hand, all of them attenuated ECS-induced alterations but to a variable extent and with different patterns, indicating potential preventive efficacy. The main ECS-altered functions that were modulated by chemopreventive agents included cell proliferation, apoptosis, differentiation, Ras activation, P53 functions, NF-kappaB pathway, transforming growth factor-related stress response, and angiogenesis. Some microRNAs known to be polymorphic in humans were downregulated by ECS and were protected by chemopreventive agents. This study provides proof-of-concept and validation of technology that we are further refining to screen and prioritize potential agents for continued development and to help elucidate their biological effects and mechanisms. Therefore, microRNA analysis may provide a new tool for predicting at early carcinogenesis stages both the potential safety and efficacy of cancer chemopreventive agents.
- SourceAvailable from: James Edward Trosko
[Show abstract] [Hide abstract]
- "Indole-3-carbinole could prevent H 2 O 2 -induced inhibition of GJIC in WB-F344 cells by inhibition of Akt phosphorylation that could also prevent phosphorylation of Cx43. Most significantly, several chemopreventive agents, including indole-3-carbinol, were shown to attenuating environmental cigarette smoke-induced lesions in rat lungs (Izzotti et al. 2010). "
ABSTRACT: Dietary phytochemicals offer protection from oxidative damages and lower the risks of chronic diseases, by complementary and overlapping action mechanisms. These include antioxidant activity, regulation of gene expression and cell cycle, stimulation of the immune and hormonal systems and modulation of cell–cell communication. Gap-junction intercellular communication (GJIC) plays an important role in maintaining tissue homeostasis by allowing the intercellular exchange of ions and regulatory molecules associated with cell proliferation, differentiation and apoptosis, and by contributing to intracellular signaling. This mechanism is strictly regulated and abnormal GJIC can result in several pathological conditions. GJIC is deregulated in cancer cells and reversible GJIC inhibition is strongly related to the promotion phase of carcinogenesis, likely mediated by reactive oxygen species. Whereas, the reversible inhibition of GJIC is related to the promotion phase of carcinogenicity, enhancers of GJIC are expected to prevent cancer. Several dietary plant compounds demonstrated the ability to control GJIC at the epigenetic levels and to prevent GJIC down-regulation by tumor promoting compounds, thus preventing cancers. In this Commentary, a number of reported studies on several phytochemicals in dietary and medicinal plants, which were able to affect GJIC and their structural proteins, i.e., connexins, in different in vivo and in vitro systems, were examined. The growing evidence, on the involvement of plant-derived molecules in the modulation of GJIC and in understanding of the specific action mechanisms, might offer a new perspective of the protective and/or preventive effects of dietary phytochemicals, in addition to possible chemotherapeutic use.Phytochemistry Reviews 05/2012; 11(2-3). DOI:10.1007/s11101-012-9235-7 · 2.89 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Although microRNAs (miRNA) have extensively been investigated in cancer research, less attention has been paid to their regulation by carcinogens and/or protective factors in early stages of the carcinogenesis process. The present study was designed to evaluate the modulation of mRNA expression as related to exposure of neonatal mice to environmental cigarette smoke (ECS) and to treatment with chemopreventive agents. Exposure to ECS started immediately after birth and for 2 weeks after weaning. Thereafter, groups of mice received daily either budesonide (BUD) or phenethyl isothiocyanate (PEITC) with the diet. The expression of 576 miRNAs was evaluated by miRNA microarray in liver and lung. In sham-exposed mice, the expression of miRNAs tended to be higher in liver than in lung. ECS downregulated the expression of a number of miRNAs in lung, whereas mixed alterations were observed in liver. PEITC and BUD did not substantially affect the physiological situation in lung, whereas both agents caused intense variations in liver, reflecting the occurrence of damage mechanisms, such as inflammation, DNA and protein damage, cellular stress, proliferation and apoptosis. PEITC and BUD protected the lung from ECS-induced alterations of miRNA expression but exhibited some adverse effects in liver. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] /* */Carcinogenesis 02/2010; 31(5):894-901. DOI:10.1093/carcin/bgq037 · 5.27 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: MicroRNAs (miRNAs) are important regulators of gene expression. Alteration of miRNA expression caused by exposure of different carcinogens has been well reported. This review aims to present the miRNAs dysregulated by exposure of different types of carcinogens in different biological systems and to discuss their potential roles in different stages of chemical carcinogenesis, following an introduction of miRNA biogenesis, regulatory mechanisms, and target identification. Available information shows that expression of a large number of miRNAs is readily changed by exposure of carcinogens in tissue- and chemical-specific manners. Carcinogenic agents generally induce many more changes in miRNA expression than non-carcinogenic chemicals. There are many more changes in cancer-target tissues than in the non-target tissues after acute or chronic exposure to carcinogens. Many of the miRNAs deregulated by carcinogens are involved in regulation of genes that are important for every stage of chemical carcinogenesis, including xenobiotic metabolism, carcinogen-induced hypomethylation, DNA repair, apoptosis, cell proliferation, tumor suppression, cell transformation, oncogenesis, tumor angiogenesis, tumor progress, mangliant transformation, and other functions. Many miRNAs function as putative oncogenes and tumor suppressor genes. The carcinogenic functions of carcinogens may be dependent on the balance between tumor-suppressor miRNAs and oncogenic miRNAs. Thus, the miRNA profiles and miRNAs specific to carcinogen exposure have the potential to be used as biomarkers for identifying genotoxicity and carcinogenicity of chemicals and indicating exposure of carcinogens.Journal of Environmental Science and Health Part C Environmental Carcinogenesis & Ecotoxicology Reviews 04/2010; 28(2):89-124. DOI:10.1080/10590501.2010.481477 · 2.50 Impact Factor