title: Impact of Genetic Variation in MicroRNA-binding Site on Susceptibility to Colorectal Cancer.
abstract: The present study analyzed single nucleotide polymorphisms (SNPs) located at putative microRNA(miRNA)-binding sites of the 3'-untranslated region (UTR) in different genes and investigated their impact on the susceptibility to colorectal cancer (CRC). Ninety-two SNPs were selected using an in silico analysis of 3'-UTR SNPs in an SNP database and their miRNA binding efficiency was calculated using several miRNA databases and the HapMap database. Two independent study sets were used: 380 healthy controls and 371 patients with colorectal adenocarcinoma for the discovery set, and 521 healthy controls and 524 patients with colorectal adenocarcinoma for the validation set. The SNP genotyping was performed using a Sequenom MassARRAY. In addition, a luciferase assay was used to investigate whether miR-370 modulated docking protein 3 (DOK3) gene expression when rs2279398G>A was included in the DOK3 3'-UTR region. For the discovery set, 16 out of 92 SNPs were significantly associated with the risk of CRC in at least one of the genetic models. The validation set showed that among these 16 SNPs, DOK3 rs2279398G>A was significantly associated with reduced risk of CRC in a recessive model [adjusted odds ratio (aOR)=0.65, 95% confidence interval (CI)=0.44-0.97, p=0.03]. In a combined analysis, DOK3 rs2279398G>A was associated with a significantly reduced risk of CRC in a co-dominant and recessive model (aOR=0.84, 95% CI=0.73-0.96, p=0.012; aOR=0.65, CI=0.49-0.88, p=0.004, respectively). Significantly lower Renilla activity was also observed with the rs2279398 AA construct when compared to the rs2279398 GG construct (p<0.001). DOK3 rs2279398G>A may affect the expression of DOK3 by altering the miRNA binding efficiency at the miRNA-binding sites of the 3'-UTR in DOK3, thereby impacting CRC tumorigenesis.
authors.affiliation: Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Cancer Research Institute, Daegu, Republic of Korea.
authors.forename: Byung Woog
authors.initials: BW
authors.lastname: Kang
authors.affiliation: M monitor Inc., Daegu, Republic of Korea jkk21c@knu.ac.kr jeonh@knu.ac.kr.
authors.forename: Hyo-Sung
authors.initials: HS
authors.lastname: Jeon
authors.affiliation: Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Cancer Research Institute, Daegu, Republic of Korea.
authors.forename: Yee Soo
authors.initials: YS
authors.lastname: Chae
authors.affiliation: Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Cancer Research Institute, Daegu, Republic of Korea.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Surgery, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Jun Seok
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Surgery, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Gyu Seog
authors.initials: GS
authors.lastname: Choi
authors.affiliation: Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Cancer Research Institute, Daegu, Republic of Korea jkk21c@knu.ac.kr jeonh@knu.ac.kr.
authors.forename: Jong Gwang
authors.initials: JG
authors.lastname: Kim
mesh_terms: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000368:Aged; D001665:Binding Sites; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; C518789:DOK3 protein, human; C526503:MIRN370 microRNA, human; D035683:MicroRNAs
keywords: Colorectal cancer; DOK3; microRNA target gene; polymorphism; susceptibility