Matrix Metalloproteinase-1 (MMP-1) Promoter Polymorphisms are Well Linked with Lower Stomach Tumor Formation in Eastern Indian Population

Abstract

Expression of matrix metalloproteinase-1 (MMP-1), an interstitial collagenase, plays a major role in cellular invasion during development of gastric cancer, a leading cause of death worldwide. A single-nucleotide polymorphism (SNP) −1607 1G/2G site of the MMP-1 gene promoter has been reported to alter transcription level. While the importance’s of other SNPs in the MMP-1 promoter have not yet been studied in gastric cancer, our aim was to investigate MMP-1 gene promoter polymorphisms and gastric cancer susceptibility in eastern Indian population. A total of 145 gastric cancer patients and 145 healthy controls were genotyped for MMP-1 −1607 1G/2G (rs1799750) by PCR-restriction fragment length polymorphism (RFLP), while MMP-1 −519 A/G (rs1144393), MMP-1 −422 T/A (rs475007), MMP-1 −340 T/C (rs514921) and MMP-1 −320 T/C (rs494379) were genotyped by DNA sequencing. A positive association was found with MMP-1 −422 T/A SNP that showed significant risk for regional lymph node metastasis (P = 0.021, Odd’s ratio (OR) = 3.044, Confidence intervals (CI) = 1.187–7.807). In addition, we found a significant association with lower stomach tumor formation among gastric cancer patients for three adjacent polymorphisms near the transcriptional start sites of [MMP-1 −422 T/A (P = 0.043, OR = 2.182, CI = 1.03–4.643), MMP-1 −340 T/C (P = 0.075, OR = 1.97, CI = 0.94–4.158) and MMP-1 −320 T/C (P = 0.034, OR = 2.224, CI = 1.064–40731)]. MMP-1 level in patients’ serum was correlated with MMP-1 promoter haplotypes conferring these three SNPs to evaluate the functional importance of these polymorphisms in lower stomach tumor formation and significant correlation was observed. Furthermore, MMP-1 −519 A/G polymorphism displayed poor cellular differentiation (P = 0.024, OR = 3.8, CI = 1.69–8.56) attributing a higher risk of cancer progression. In conclusion, MMP-1 proximal promoter SNPs are associated with the risk of lower stomach tumor formation and node metastasis in eastern Indian population.

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

“…Bradbury et al [51] reported an elevated esophageal cancer risk in 1G/2G and 2G/2G carrier. MMP-1 protein expression is higher in tumors from gastric cancer patients who carry the 2G allele not 1G homozygotes [52] . Moreover, 2G homozygotes are more likely to develop invasive tumors.…”

“…Moreover, 2G homozygotes are more likely to develop invasive tumors. Dey et al [52] reported that MMP-1 promoter polymorphism is significantly associated with lower stomach tumor formation. MMP-1 -1607 1G/2G polymorphism is also involved with colon cancer risks.…”

“…In addition, Zhang et al [64] found a higher ESCC risk among smokers having the 5A allele and reported that an elevated risk of lymph node metastasis in patients having 5A allele instead of the 6A allele. Interestingly, Dey et al [52] reported that the frequency of homozygotes for the 6A allele is lower in …”

Molecular background of the regional lymph node metastasis of gastric cancer (Review)

“…MMPs are usually relatively inactive, and can be activated when tissues are undergoing repair or remodeling, or in disease or inflammation (9). It has been reported that repressing the expression of certain MMPs is associated with increased survival and favorable prognosis in GC patients (10)(11)(12). MMPs can be specifically regulated by tissue inhibitors of metalloproteinases (TIMPs).…”

Association of MMP7 −181A→G Promoter Polymorphism with Gastric Cancer Risk

“…However, the molecular basis of MMP7 up-regulation in gastric cancer remains unclear. Single base pair substitutions in the MMP promoter may create or abolish the transcription factor-binding site, thereby modifying transcriptional activity (23,24). Two common functional SNPs (Ϫ181A3 G and Ϫ153C/T) located in the MMP7 promoter region known to influence gene expression were studied in several disease conditions, including hypercholesterolemia, idiopathic pulmonary fibrosis, and several cancer types (e.g.…”