Novel Functional Variants in the Notch Pathway and Survival of Chinese Colorectal Cancer

Abstract

Background: Notch signaling pathway plays a crucial role in progression of colorectal cancer (CRC).Genetic variants in Notch pathway genes may impact the prognosis in CRC. Method: The associations genotypes of single-nucleotide polymorphisms (SNPs) from Notch pathway genes and overall survival (OS) in 1116 Chinese eastern CRC were investigated. The ChIP sequencing data from the encyclopedia of DNA Elements (ENCODE), Expression quantitative trait loci (eQTL) analysis and Dual luciferase assays were used to evaluated the association of SNPs genotype and candidate gene expression. The function of candidate gene was explored in The Cancer Genome Atlas (TCGA) CRC data and elucidated in vitro experiments. Findings: We identified MINAR1 rs72430409 was significantly associated with a greater death risk (HR=1.98, 95% CI=1.55–2.54, P=6.8×10-8). The analysis of ENCODE data showed that rs72430409 were potential cis-regulatory elements for the MINAR1 promoter, eQTL analysis revealed that rs72430409 A allele were correlated with increased MINAR1 expression. Dual luciferase assays revealed that rs72430409 A allele increased MINAR1 promoter activity. The expression of MINAR1 in TCGA CRC samples were significantly higher than that in normal colorectal tissue and high expression of MINAR1 was associated with a shortened OS, likely via activating the epithelial mesenchymal transition (EMT) pathway. RNAi mediated silencing of MINAR1 led to decreased migration and proliferation in CRC cells, and MINAR1 silencing could downregulate the expression of key effector genes in EMT and glycolysis. Interpretation:Our study identified novel functional genetic variants which could independently predicted CRC survival, the gene harbouring this loci functioned as a putative oncogene in CRC by regulating EMT and glycolysis. Funding Statement: This research was supported by Natural Science Foundation of China and Shang Shanghai Natural Science Foundation. Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: The research proposal was approved by the FUSCC institutional review board.