DR4 mediates the progression, invasion, metastasis and survival of colorectal cancer through the Sp1/NF1 switch axis on genomic locus. Issue 2 (1st March 2018)

• Record Type: Journal Article
• Authors: Wu, Shenshen; Meng, Qingtao; Zhang, Chengcheng; Sun, Hao; Lu, Runze; Gao, Na; Yang, Hongbao; Li, Xiaobo; Aschner, Michael; Chen, Rui
• Is Part Of: International journal of cancer. Volume 143:Issue 2(2018)
• Page Start: 289
• Page End: 297
• Publication Date: 2018-03-01
• Subjects: colorectal cancer -- DR4 -- development -- survival; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31318
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : The single nucleotide polymorphism (SNP), −397G > T (rs13278062) polymorphism, in the promoter of Death Receptor 4 (DR4) had been reported to be associated with a significantly increased risk for bladder cancer. However, the association of this SNP with the risk of colorectal cancer has not been reported. In this study, we performed a case–control study in 1, 078 colorectal cancer patients and 1, 175 matched healthy controls to evaluate the association of the potential functional genetic variants in DR 4 with risk and survival of colorectal cancer. PCR‐TaqMan were used to genotype the rs13278062, rs1000294 and rs2235126 polymorphisms. We found that subjects carrying the rs13278062 GT/TT genotypes had a significantly lower risk and increased survival time when compared to the GG genotype. We also constructed the rs13278062 GT/TT genotype in SW480 and SW620 cells (rs13278062 is GG in both cell lines) with the CRISPR/Cas9 system. Flow cytometry experiments showed that the rs13278062 TT genotype promoted apoptosis in colorectal cancer cells. In vitro and in vivo experiments established that the rs13278062 G to T mutation inhibited carcinogenesis and metastasis of colorectal cancer. Chromatin immunoprecipitation (ChIP) assays revealed that the rs13278062 G > T polymorphism altered the binding affinity of the transcription factors Sp1/NF1 to the rs13278062 mutation region. Immunohistochemistry, western blot, and qPCR corroborated that the rs13278062 GT/TT genotypes increased the expression of DR4 protein in colorectal cancer tissues and cells. In conclusion, these findings indicate that DR4 mediated progression, invasion, metastasis and survival of colorectal cancer via the Sp1/NF1 switch axis on genomics locus. Abstract : What's new? Death receptor 4 (DR4) is a cell protein that can activate apoptosis (programmed cell death). Abnormal expression of DR4 is associated with poor prognosis in colorectal cancer (CRC). In this study, the authors found that when a particular SNP in the DR4 gene contained GT/TT, patients had a decreased risk of CRC and increased survival times compared to the GG genotype. The authors then used CRISPR/Cas9 to change GG to GT in CRC cells, and found that this change promoted apoptosis and inhibited carcinogenesis and metastasis in vivo .