Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer

Abstract

Notch signaling pathway plays crucial roles in progression of colorectal cancer (CRC), likely affecting overall survival (OS). In a two‐stage survival analysis of 1116 CRC patients in East China, we found that one locus at MINAR1 out of 133 genes in the Notch signaling pathway was significantly associated with OS (P < 1 × 10−6, false discovery rate < 0.01). This locus containing seven single‐nucleotide polymorphisms (SNPs) in high linkage disequilibrium (R2 = 1) is located on chromosome 15, of which the MINAR1 rs72430409 G allele was associated with a greater death risk (HR = 1.98, 95% CI = 1.55‐2.54, P = 6.8 × 10−8). Further analysis of ChIP‐sequencing data from the encyclopedia of DNA Elements showed that rs72430409 and rs72630408 were potential cis‐regulatory elements for the MINAR1 promoter. Additional expression quantitative trait loci analysis revealed that rs72430409 G>A and rs72630408 A>G were correlated with increased MINAR1 expression levels in both blood cells and colon tissues. Dual luciferase assays revealed that the rs72430409 A allele increased MINAR1 promoter activity. The Cancer Genome Atlas data showed that expression levels of MINAR1 in CRC samples were significantly higher than that in normal colorectal tissue and that high expression of MINAR1 was associated with a shortened OS, likely via activating the epithelial mesenchymal transition (EMT) pathway as shown in the gene‐set enrichment analysis. In vitro, RNAi‐mediated silencing of MINAR1 led to decreased migration and proliferation in CRC cancer cells, and MINAR1 silencing could downregulate the expression of key effector genes in EMT and glycolysis. Larger cohort studies and further experiments are needed to validate our findings.

Interplay between Signaling Pathways and Tumor Microenvironment Components: A Paradoxical Role in Colorectal Cancer

“…Recently, the analysis of the Notch signaling pathway of 1116 CRC patients in East China highlighted that one locus at MINAR1 out of 133 genes is significantly associated with overall survival. This study proves that the Notch pathway plays a crucial role in the progression of CRC, likely affecting patient survival [ 56 ]. Moreover, in CRC patients, it has been reported that mutations in the Notch pathway components can activate anti-tumor immune responses, which are characterized by the up-regulation of checkpoint molecules [ 57 ].…”

Identification and validation of a novel prognosis model based on m5C-related long non-coding RNAs in colorectal cancer

“…Dysregulation of p53 function can be detected in approximately 90% of cancers, including TP53 mutations or abnormal activation of other upstream factors [ 61 ]. The NOTCH_SIGNALING_PATHWAY played a key role in the progression of colorectal cancer (CRC), which may affect overall survival (OS) [ 62 ]. NOVA1-mediated SORBS2 promoted the migration of CRC by Activating the Notch Pathway, indicating its potential as a therapeutic target.…”

Signaling pathways in colorectal cancer: implications for the target therapies

“…Inhibiting DAB1/ Dab1, a gene activated by Notch signaling, reduces tumor invasion in colon cancer models [155]. Elevated Notch expression levels negatively predict overall survival (OS), with Notch1 positively correlating with tumor stage in histological findings [156,157]. Crosstalk between Notch and Wnt pathways has been observed; Notch inhibition promotes liver-specific tumor growth by upregulating the Wnt/β-catenin signaling pathway and enhancing pro-tumor cytokine production from Kupffer cells, similar to tumor-associated macrophages [158].…”