Title: MPO Promoter Polymorphism rs2333227 Enhances Malignant Phenotypes of Colorectal Cancer by Altering the Binding Affinity of AP-2α.
Authors: Meng, Qingtao; Wu, Shenshen; Wang, Yajie; Xu, Jin; Sun, Hao; Lu, Runze; Gao, Na; Yang, Hongbao; Li, Xiaobo; Tang, Boping; Aschner, Michael; Chen, Rui
Published In Cancer Res, (2018 05 15)
Abstract: Myeloperoxidase (MPO) promoter SNPs rs2243828 (-764T>C) and rs2333227 (G-463A) program malignant phenotypes by regulating MPO transcriptional activity. In this study, we enrolled a total of 1,175 controls and 1,078 patients with colorectal cancer with comprehensive clinical and survival information to assess whether these SNPs could affect the susceptibility and development of colorectal cancer. The MPO rs2333227 TT genotype significantly increased the risk of colorectal cancer and decreased the overall survival time of patients. Colorectal cancer cells with the rs2333227 TT genotype exhibited enhanced proliferation, migration, and invasion capacity in vitro and in vivo Mechanistically, we found that MPO SNP rs2333227 C to T mutation altered the binding affinity of the transcription factors AP-2α to the rs2333227 mutation region, sequentially enhancing expression levels of MPO and activating further IL23A-MMP9 axis-mediated oncogenic signaling. Taken together, our findings indicate that MPO SNP rs2333227 serves as a marker of enhanced risk for development of colorectal cancer.Significance: MPO polymorphisms are a guide for high risk and poor prognosis in patients colorectal cancer. Cancer Res; 78(10); 2760-9. ©2018 AACR.
PubMed ID: 29540402
MeSH Terms: Animals; Case-Control Studies; Cell Line, Tumor; Cell Movement/genetics; Cell Proliferation/genetics; China; Colorectal Neoplasms/genetics*; Colorectal Neoplasms/mortality; Colorectal Neoplasms/pathology; Female; Genetic Predisposition to Disease/genetics*; Humans; Interleukin-23 Subunit p19/metabolism; Male; Matrix Metalloproteinase 9/metabolism; Mice; Mice, Nude; Neoplasm Transplantation; Peroxidase/genetics*; Polymorphism, Single Nucleotide/genetics*; Prognosis; Promoter Regions, Genetic/genetics*; Protein Binding/genetics; Transcription Factor AP-2/genetics; Transcription Factor AP-2/metabolism; Transplantation, Heterologous