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.
Highlights
Gastric cancer is one of the leading causes of cancer related death in the world [1]
Being a member of Matrix metalloproteinases (MMPs) family, matrix metalloproteinase-1 (MMP-1) has been reported to play an important role in cancer invasion through overexpression, which is associated with metastasis and poor prognosis in esophageal cancer, ovarian cancer, cutaneous malignant melanoma, colorectal cancer and gastric cancer [11,15,16,25,34]
Diffuse types of gastric cancer are usually characterized by an abundant deposition of collagen fibers, possibly requiring higher levels of MMP-1 expression for proper tissue remodeling of the microenvironment [30]
Summary
Gastric cancer is one of the leading causes of cancer related death in the world [1]. More than 70% of GC cases occur in developing countries and half the world total occurs in Eastern Asia [1]. It is a leading problem in northeastern and southern states of the Indian subcontinent [2]. Helicobacter pylori infection is considered as a major risk factor in the development of gastric cancer especially cancer in the lower part (noncardia) of the stomach [3]. A combined analysis of 12 studies of H. pylori and gastric cancer estimated that the risk of adenocarcinoma in non-cardia regions of the stomach was nearly six times higher for H. pylori-infected people than for uninfected people [3]
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