Prognostic implications of TIMP1 gene expression in colon Adenocarcinoma: structural and functional consequences of non-synonymous SNP variants

Abstract

The investigation into single nucleotide polymorphism (SNP) mutations within the TIMP1 gene, particularly in the context of colon cancer, is a topic of considerable scientific research. Numerous studies emphasize the pivotal role of TIMP1 in the promotion of tumorigenesis and metastasis in human colon cancer, positioning it as a potential prognostic marker and therapeutic target. Identifying polymorphisms influencing the structure and function of the TIMP1 gene is crucial. In this study, we pinpointed damaging non-synonymous SNPs (nsSNPs) among 2130 SNPs, with rs192373432 (R192W), rs145224385 (R203W), and rs199775125 (T171M) identified as deleterious, probably damaging, and exposed, respectively. Notably, the R203W substitution demonstrated the highest destabilizing effect (DDG value: -0.92872 Kcal/mol), indicating a more significant impact on protein stability than the other variants (R192W: -0.20284 Kcal/mol, T171M: -0.07699 Kcal/mol). Molecular dynamics simulations revealed that the R192W mutation results in a more rigid, compact, and structurally stable protein with reduced flexibility and fewer hydrogen bonds compared to the wild type, which might affect its functional interactions and stability. The 2D projection of the trajectory indicated that the mutant occupies a more constrained conformational space, reinforcing its rigid nature. The protein interaction network revealed associations with extracellular matrix remodeling (MMP1, MMP2, MMP3, MMP9, MMP10), inflammation (IL6, IL10), and immune response (CD63, FN1), offering insights into TIMP1’s potential mechanisms in colon cancer and identifying new therapeutic targets. Analysis of TIMP1 gene expression and survival in Colon Adenocarcinoma (COAD) unveiled a dual association, where both overexpression and downregulation of TIMP1 correlated with patient survival. Further research is essential to comprehensively understand the regulatory role of these genes on TIMP1 and their impact on colon cancer development and progression.