How Diet Intervention via Modulation of DNA Damage Response through MicroRNAs May Have an Effect on Cancer Prevention and Aging, an in Silico Study.

Dario Coletti,Luigi Campanella,Laura Teodori,Maria Albertini,Zbigniew Darzynkiewicz,Alessandra Vilmercati,Felicia Carotenuto

doi:10.3390/ijms17050752

Abstract

The DNA damage response (DDR) is a molecular mechanism that cells have evolved to sense DNA damage (DD) to promote DNA repair, or to lead to apoptosis, or cellular senescence if the damage is too extensive. Recent evidence indicates that microRNAs (miRs) play a critical role in the regulation of DDR. Dietary bioactive compounds through miRs may affect activity of numerous genes. Among the most studied bioactive compounds modulating expression of miRs are epi-gallocatechin-3-gallate, curcumin, resveratrol and n3-polyunsaturated fatty acids. To compare the impact of these dietary compounds on DD/DDR network modulation, we performed a literature search and an in silico analysis by the DIANA-mirPathv3 software. The in silico analysis allowed us to identify pathways shared by different miRs involved in DD/DDR vis-à-vis the specific compounds. The results demonstrate that certain miRs (e.g., -146, -21) play a central role in the interplay among DD/DDR and the bioactive compounds. Furthermore, some specific pathways, such as “fatty acids biosynthesis/metabolism”, “extracellular matrix-receptor interaction” and “signaling regulating the pluripotency of stem cells”, appear to be targeted by most miRs affected by the studied compounds. Since DD/DDR and these pathways are strongly related to aging and carcinogenesis, the present in silico results of our study suggest that monitoring the induction of specific miRs may provide the means to assess the antiaging and chemopreventive properties of particular dietary compounds.

Highlights

The DNA in each of our cells accumulates thousands of lesions every day
DIANA-miRPath v3.0 was used to predict the targeted Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways by miRs involved in DNA damage response (DDR) signaling and that were EGCG modulated
DIANA-miRPath v3.0 was used to predict the targeted KEGG pathways by miRs involved in DDR signaling and that were CRC modulated

Summary

Introduction

The DNA in each of our cells accumulates thousands of lesions every day. Cells are continuously challenged by DNA damage stimuli from various exogenous environmental factors, such as ultraviolet (UV) radiation, ionizing radiation (IR) and numerous chemical agents, or endogenous sources mainly represented by products of cellular metabolism. Multiple miRs may target the same miR, and the majority of miRs contain multiple binding sites for miRs, generating a highly complex regulatory network system by which hundreds of genes involved in different signaling pathways can be regulated simultaneously [14] Nutrients and their bioactive compounds can modulate the miRs’ expression involved in many physiological and pathological processes [15]. Sci. 2016, 17, 752 eicosapentaenoic acid (EPA); and docosahexaenoic acid (DHA) Each of these four dietary compounds, at a concentration that potentially may be achievable in the organism, has been shown to suppress cell proliferation and induce apoptosis in certain types of human cancer cells [18,19]. The results of the analysis of the pathways allowed us to speculate how food intervention could modulate DD/DDR

Results

DDisisccuusssioionn

Search Strategy and Selection Criteria

In Silico Analysis