Abstract
Background: The tissue inhibitors of metalloproteinases (TIMPs) including TIMP2 and TIMP3 are the key physiological inhibitors of matrix metalloproteinases (MMPs) and along with MMPs, TIMPs play a vital role in the coordinated proteolytic breakdown and remodeling of the extracellular matrix (ECM) and the basement membrane that represent the barriers to any malignant tumor invasion and progression. These enzymes are vital for tumor invasion and metastasis and also play a critical role in several other stages of tumor development and progression. The studies on the association of various polymorphisms in human TIMP2 and TIMP3 genes including TIMP2-418G/C and TIMP3-1296T/C single nucleotide polymorphisms (SNPs) and CRC risk are limited, mixed, and inconclusive.Materials and methods: The aim of the present study was to analyze the association of TIMP2-418G/C and TIMP3-1296T/C promoter SNPs with colorectal cancer (CRC) susceptibility and development risk and also to evaluate the modifying effects of possible TIMP2-418G/C and TIMP3-1296T/C SNPs’ genotypes on different risk factors of CRC or the reciprocal effect in ethnic population of Kashmir, India through a case–control setup. The genotype frequencies of TIMP2-418G/C and TIMP3-1296T/C promoter SNPs were compared between 142 CRC patients and 184 individually matched healthy controls by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The associations between the TIMP2-418G/C and TIMP3-1296T/C SNPs and CRC risk were examined through conditional logistic regression models adjusted for multiple possible confounding (third) variables. The possible effect measure modification of the association between the relevant SNP genotypes and CRC risk by various CRC risk factors including age, gender, and smoking status was also analyzed. Further, the associations between these SNPs and various clinico-pathological parameters, demographic variables, and environmental factors within the case group subjects with regard to CRC risk were also evaluated.Results: The overall association between the TIMP2-418G/C and TIMP3-1296T/C SNPs and the modulation of CRC risk was found to be highly significant (P=0.019 and P=0.000 for TIMP2 and TIMP3 SNPs, respectively). The heterozygous genotype (GC) of TIMP2-418G/C was significantly associated with an increased risk of colorectal cancer [OR, 1.87 (95%CI, 1.07–3.27); P=0.027] whereas the heterozygous genotype (TC) of TIMP3-1296T/C SNP was significantly associated with a decreased risk of colorectal cancer [OR, 0.53 (95%CI, 0.32–0.86); P=0.011]. The variant genotype (CC) of TIMP3-1296T/C SNP was also significantly associated with a decreased risk of colorectal cancer [OR, 0.18 (95%CI, 0.05–0.65); P=0.009].Conclusion: The present study demonstrates that there is a strong and highly significant association between the TIMP2-418G/C and TIMP3-1296T/C promoter SNPs and the risk of developing CRC in ethnic Kashmiri population. However, in order to substantiate our findings, the present study needs to be replicated with bigger sample size and should involve other ethnically defined populations with high CRC risk.
Highlights
Colorectal cancer (CRC) defined as the neoplasia of the colon, rectum, and appendix is the third most common cause of cancer-related morbidity and mortality worldwide with nearly 1.2 million new cases diagnosed each year and approximately 600,000 deaths reported annually [1,2]
The functional significance of this single nucleotide polymorphism (SNP) is not fully known yet but it has been proposed that TIMP2-418 G to C transition abolishes the binding site of transcriptional activator, Sp1 and the C allele may be associated with a markedly diminished promoter activity and reduced transcription which may result in decreased TIMP2 gene expression and eventually decreased TIMP2 activity and function including the inhibition of matrix metalloproteinase (MMP) [36,37]
It is possible that TIMP2-418G/C SNP induced down-regulation may alter tissue inhibitors of metalloproteinase (TIMP) MMP and non-MMP functions and disturb the physiological equilibrium between MMPs and TIMPs resulting in altered TIMP function including decreased inhibition and increased MMP activity which leads to altered extracellular matrix (ECM) homeostasis and other physiological alterations which are critical events in neoplastic progression including that of CRC as discussed earlier [5,9,10,12]
Summary
Colorectal cancer (CRC) defined as the neoplasia of the colon, rectum, and appendix is the third most common cause of cancer-related morbidity and mortality worldwide with nearly 1.2 million new cases diagnosed each year and approximately 600,000 deaths reported annually [1,2]. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases and their physiological inhibitors that regulate the activity of MMPs, in particular, the tissue inhibitors of metalloproteinases (TIMPs) are key players in the coordinated proteolytic breakdown and remodeling of the ECM and the basement membrane which besides making them important for several physiological processes makes them vital for tumor invasion and metastasis [5,6] They play a critical role in several other stages of tumor development and progression. Materials and methods: The aim of the present study was to analyze the association of TIMP2-418G/C and TIMP3-1296T/C promoter SNPs with colorectal cancer (CRC) susceptibility and development risk and to evaluate the modifying effects of possible TIMP2-418G/C and TIMP3-1296T/C SNPs’ genotypes on different risk factors of CRC or the reciprocal effect in ethnic population of Kashmir, India through a case–control setup. The heterozygous genotype (GC) of TIMP2-418G/C was significantly associated with an increased risk of colorectal cancer [OR, 1.87 (95%CI, 1.07–3.27); P=0.027] whereas the heterozygous genotype (TC) of TIMP3-1296T/C SNP was significantly associated with a decreased risk of colorectal cancer [OR, 0.53 (95%CI, License 4.0 (CC BY)
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