title: Identification of microRNAs regulated by isothiocyanates and association of polymorphisms inside their target sites with risk of sporadic colorectal cancer.
abstract: Sporadic colorectal cancer (CRC) is a typical multifactorial disease. Isothiocyanates (ITC) have been recently shown to inhibit development of CRC in many experimental models. MicroRNAs (miRNAs) are short noncoding RNAs that posttranscriptionally regulate gene expression through binding to 3' untranslated regions (3'UTR) of target mRNAs. MiRNAs are regulated by natural agents, ITCs included. In our study, using global expression profiling based on TaqMan Low-Density Arrays, we identified 3 common miRNAs (miR-155, miR-23b, miR-27b) regulated by ITCs (sulforaphane, iberin) in colonic epithelial cell lines NCM460 and NCM356. In silico predictions allowed us to find 9 relevant single nucleotide polymorphisms (SNPs) localized within the 3'UTRs of genes (AGTR1, TNFAIP2, PRKCB, HSPA9, RABGAP1, DICER1, ADAM19, VWA5A, and SIRT5) targeted by these ITC-related miRNAs. Finally, we observed that homozygous CC genotype of DICER1, rs1057035, was significantly associated with decreased risk of CRC (odds ratio = 0.49; 95% confidence interval: 0.25-0.95, P = 0.036) when compared to TT homozygote genotype; also, the C allele tended to have a protective effect (P = 0.072). This study showed that miRNAs could be involved in chemoprotective effects of natural agents; their function alteration through SNPs in their binding sites and flanking regions presents a new class of CRC risk factors.
authors: Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Brno, Czech Republic. on.slaby@gmail.com
authors: Ondrej
authors: O
authors: Slaby
authors: Milana
authors: M
authors: Sachlova
authors: Veronika
authors: V
authors: Brezkova
authors: Renata
authors: R
authors: Hezova
authors: Alena
authors: A
authors: Kovarikova
authors: Svatava
authors: S
authors: Bischofová
authors: Sabina
authors: S
authors: Sevcikova
authors: Julie
authors: J
authors: Bienertova-Vasku
authors: Anna
authors: A
authors: Vasku
authors: Marek
authors: M
authors: Svoboda
authors: Rostislav
authors: R
authors: Vyzula
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D002460:Cell Line / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics*; D003198:Computer Simulation; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020011:Protective Agents / Q000494:pharmacology; D043244:Ribonuclease III / Q000235:genetics*; D013454:Sulfoxides
chemical_list: D020413:3' Untranslated Regions; D017879:Isothiocyanates; C524942:MIRN155 microRNA, human; C552430:MIRN23a microRNA, human; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D020011:Protective Agents; D013454:Sulfoxides; C082585:iberin; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; C016766:sulforaphane