COAD is one of the most leading cause of human death in the world. Early detection of SNP mutations was conducted to find meaningful biological markers to predict the occurrence and development of tumors. (4) (5) (6) After functional enrichment and pathway analysis, researchers began to further study the molecular mechanisms of these mutated genes.
In our study, we screened out SNP mutated genes through bioinformatics analysis of coad-related genes based on TCGA data. Functional enrichment and pathway analysis were performed to further investigate the direct involvement of mutated genes in relevant molecular mechanisms. Outside the cell, genes accumulate in the matrix and collagen−containing extracellular matrix. The genes basically coordinate the transmission of signals, such as the formation of new synapses, cell adhesion, and actin binding. According to the results of pathway analysis, these mutated genes are related to the pi3k-akt signaling pathway, calcium signaling passage and focal adhesion, and that these pathways were associated with tumor evolution. The enrichment function and the study of the pathway reveal the molecular mechanism of SNP mutations in disease progression. The express levels about the four hub genes (CTTNBP2, DAPK1, DMXL2, SPTBN2) were significantly different from those of the wild type. The expression of these genes was also significantly correlated with patient prognosis. Analysis of coexpression, drug sensitivity and multiple levels of immune infiltration of these core genes can better help us understand how they affect the prognosis of patients.
CTTNBP2 can influence the shape and number of dendritic spines (14). CTTNBP2 also plays a role in other tissues, including the binding of the rad21 - cohesive protein complex (15). For prostate cancer, specifically, CTTNBP2 is located in a gene block on chromosome 7, a gene with differential methylation in the prostate cancer cell line (16). Our study indicated that the low expression of CTTNBP2 gene meaned that patients with COAD had a worse prognosis. The gene set associated with the co-expression of CTTNBP2 was significantly related to the development of tumor. For example, the overexpression of JADE3, in vivo and in vitro, the stem-like properties of colon cancer cells increased and inhibition decreased. JADE3 must be expressed, so that the tumorigenic characteristics of cancer cells in the body can reduce the damage to the human body. The promoters of the JADE3 interaction (colon cancer stem cell markers) and LGR5 promoted acetyltransferase and histone acetylation of p300 in terms of activated transcription, so significantly induced Wnt/jp-catenin signaling to some extent (17). For another example, NORAD (Non-Coding RNA Activated By DNA Damage) is an RNA Gene, and is affiliated with the lncRNA class. The diseases associated with NORAD include pancreatic cancer and bladder cancer. NORAD is one of the independent prognostic factors for each patient with PDAC, which can promote the metastasis and invasion of PDAC in vivo and in vitro. (18). Particularly, NORAD may act as ceRNA and control the expression of RhoA, a small GTP binding protein, by competing for hsa-mir-125a-3p, thereby promoting the generation of EMT. (18) In our study, CTTBNBP2 is involved in multiple tumor pathways. Its expression inhibits cell apoptosis and cell cycle. This suggests that its low expression predicts a worse prognosis.
DAPK1 (Death Associated Protein Kinase 1) is a Protein encoding gene. Diseases such as pancreatic ductal adenocarcinoma and cervical squamous cell carcinoma are associated with DAPK1 (19). Its related pathways are Cdk-mediated phosphorylation and removal of Cdc6 and autophagy-animal . Recent studies have linked the DAPK1 to breastand colon cancer (20) (21) RNF144B related to the expression of DAPK1, Apoptosis was induced by a p53/ t53-dependent but caspase independent mechanism. Overexpression of p53RFP promoted apoptosis of wild-type HCT116 cells without p53 deletion (22) Heparinase (HPSE) is evident in a variety of malignancies: for example, the stomach, ovary, kidney, head and neck, colon, pancreas, bladder, brain, prostate, breast and liver cancer, ewing's sarcoma, multiple myeloma, and b-lymphoma (23) (24) (25) (26)
The overexpression of HPSE gene can enhance the function of vascularization. (27) Entering a vicious circle, high HPSE levels produced by cancer cells promote angiogenesis, further promoting tumor growth. The expression of DAPK1 is associated with a variety of important tumor pathways, including TSC / mTOR, RTK pathways. This is consistent with our research (Figure 8).
DMXL2 is encoded as a protein that has 12 WD domains and thus can participate in many functions, including those involved in semaphore transduction ways. Relevant studies have shown that DMXL. Aberrant Notch signaling has been linked to breast cancer formation and progression (28) (29). Normally, mTOR is one of the significant regulators of cell proliferation and division. But in tumor cells, the abnormally activated mTOR signals encouragement for tumor cells to grow, metastasize, and invade new healthy tissue (30). The overactivation of its pathway can satisfy the rapidly growing tumor cells to get more nutrients (31). Both DMXL2 and DAPK1 genes are involved in the activation of this pathway.
SPTBN2 (Spectrin Beta) is a protein-encoded genotype. SPTBN2 stabilizes glutamate transporters on the surface of cell membranes, and EAAT4 regulates the glutamate signaling way. High expression of SPTBN2 means that patients with colon cancer have a worse prognosis. Relevant reports have shown that gene PLXNA1, which is significantly co-expressed with gene SPTBN2, is involved in the MAPK pathway. Silencing the expression of gene A can enhance cell apoptosis in esophageal squamous cell carcinoma, block cell cycle, inhibit cell growth, removal, and invade (32).Immunoin filtration analysis showed that the expressions of DAPK1 and DMXL2 DAPK1 and DMXL2 are likely to play an significant role in the research of immune cell infiltration and is a biomarker for the prognosis of patients with colon cancer.