Silvio De Flora, a professor in the department of health sciences at the University of Genoa, Italy, and his colleagues report their study of microRNA modulation by chemopreventive agents in non-malignant tissues of rats exposed to environmental cigarette smoke. Using microarray analyses for 484 micro-RNAs and qPCR for a selected miRNA, they found that certain chemopreventive agents modulated ECS-altered p53 function, Ras activation, the NF-kB pathway, and apoptosis, among other processes. Genome Technology's Tracy Vence caught up with De Flora to discuss his work, published in the January issue of Cancer Prevention Research.
Genome Technology: You write that the pathogenic role of miRNAs has become well-studied in cancer research. Why is it that, as you write, "less attention has been paid to the possible occurrence of miRNA alterations in healthy tissues as a consequence of exposures to environmental and lifestyle factors"?
Silvio De Flora: Usually, miRNA expression profiles are evaluated in the neoplastic mass. Since our institutional mission is preventive medicine, we prefer to evaluate them in apparently healthy tissues as a response to noxious agents, such as cigarette smoke. In such a way, we try to predict the evolution towards the disease by assessing early molecular alterations. These alterations may have a dual meaning: they can reflect either the occurrence of defense and adaptive mechanisms, or reflect the trigger of mechanisms involved in the pathogenesis of the disease.
GT: Why did you choose the chemopreventive agents that you did?
SDF: The chemopreventive agents tested included both agents of natural origin and pharmacological agents that, in the framework of our collaborative studies with NCI, we had already used in studies on smoke-related nucleotide alterations, multi-gene expression, and proteome alterations.
GT: How did you analyze the efficacy of the applied compounds?
SDF: We evaluated the early effects of drugs and dietary principles used as chemopreventive agents in healthy tissues. We used a similar approach by evaluating other molecular end-points, such as DNA alterations, gene expression, and proteome profiles. Our general principle and working hypothesis is that a chemopreventive agent should not excessively alter molecular end-points when given alone — as an indicator of safety — but it should be able to inhibit the alterations induced by noxious agents, as an indicator of efficacy.
GT: Which compounds — or combinations of them — appeared to be most effective?
SDF: It is difficult to state which is the most effective agent, since sometimes the agents that appear to be most effective in preventing smoke-induced miRNA alterations do not appear to approach the physiological situation. The best compromise was achieved with BF [5,6-benzoflavone] and OPZ [oltipraz].
GT: What are your plans for testing these compounds further?
SDF: At present, we are testing a series of other compounds for modulation of miRNA profiles and, in parallel, for inhibition of smoke-induced lung tumors.