The functional polymorphism in the matrix metalloproteinase-7 promoter increases susceptibility to esophageal squamous cell carcinoma, gastric cardiac adenocarcinoma and non-small cell lung carcinoma

Abstract

An A to G transition at the 181 base pair position upstream of the transcription initiation site of the matrix metalloproteinase-7 (MMP-7) gene (-181A/G) may modify the development and progression of some diseases via influencing the transcription activity of the promoter. To assess the effects of the functional single nucleotide polymorphism on cancer susceptibility and progression, the MMP-7 -181A/G genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis among 258 patients with esophageal squamous cell carcinoma (ESCC), 201 patients with gastric cardiac carcinoma (GCA), 243 patients with non-small cell lung carcinoma (NSCLC) and 350 healthy individuals without cancer. The result showed that the frequency of the -181G allele in ESCC, GCA and NSCLC patients was significantly higher than that in healthy controls (P = 0.019, 0.023 and 0.004, respectively). Compared with the A/A genotype, genotypes with the -181G allele (A/G + G/G) significantly increased susceptibility to all three tumors, with adjusted odds ratio of 1.83 (95% CI = 1.12-2.99) for ESCC, 1.96 (95% CI = 1.17-3.29) for GCA and 2.00 (95% CI = 1.23-3.24) for NSCLC. Stratification analysis showed that smoking did not significantly influence the association between the MMP-7-181A/G and GCA or NSCLC, while the -181G allele only significantly increased susceptibility to ESCC among smokers. In addition, association between the -181G allele and susceptibility to ESCC and GCA showed significance only among individuals with family history of upper gastrointestinal cancer. The correlation of the MMP-7-181A/G polymorphism with potential of lymphatic metastasis was not observed in all three tumors. The study suggested that, the MMP-7-181A/G polymorphism might be a candidate marker for predicting individuals who are at higher risk to certain tumors but might not be used to predict potential of lymphatic metastasis in ESCC, GCA and NSCLC.

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer

“…Matrix metalloproteinase-7 À181A4G was the only polymorphism differently distributed among gastric carcinoma patients compared with control subjects: AA 43.0%, AG 46.8%, and GG 10.1% in patients vs AA 27.2%, AG 62.7% and GG 10.1% in controls (Po0.04; Table 2). Comparison of the genotype distribution of our Caucasian control subjects with those published on other mainly Asiatic control groups (Wollmer et al, 2002;Ghilardi et al, 2003;Krex et al, 2003;Miao et al, 2003;Wang et al, 2004;Zhou et al, 2004;Matsumura et al, 2005;Zhang et al, 2005) showed significant differences for MMP-2 À1306C4T , MMP-7 À181A4G , TIMP-1 372C4T and TIMP-2 À418G4C (Table 3). All the SNPs were evaluated for association with the clinicopathological parameters.…”

“…The only SNP that was distributed significantly differently among gastric carcinoma patients compared to our control population was MMP-7 À181A4G , with more patients of the AA genotype than in controls. The latter was not expected from previous studies on gastrointestinal cancer (Ghilardi et al, 2003;Zhang et al, 2005) and is most likely caused by ethnic differences (Asiatic vs Caucasian; Table 3), disease localisation (gastric vs colon) and the relatively low number of patients included in the studies. In our study, the gastric cancer patients with the variant AG/GG genotype showed worse survival data than the AA patients (Table 4 and Figure 1B), although the difference did not fully reach statistical significance.…”

“…Furthermore, the frequency of a functional SNP of MMP-7 (À181A4G) was found to be significantly higher in gastric cardiac carcinoma patients compared to controls in another Chinese study (Zhang et al, 2005). Particularly, genotypes with the MMP-7 À181G allele (A/G þ G/G) showed a significantly increased susceptibility for gastric cardiac carcinoma with an odds ratio of 1.96 (Zhang et al, 2005). Finally, a significant association in Japanese gastric cancer patients was found between an SNP in the promoter of the MMP-9 gene (À1562C4T) and the degree of tumour invasion, clinical stage and lymphatic invasion (Matsumura et al, 2005).…”

“…For instance, a functional SNP in the MMP-2 gene promoter (À1306C4T) was found to be associated with the risk of the development, but not the metastatic behaviour of gastric cardia adenocarcinoma, in an ethnic Chinese population (Miao et al, 2003). Furthermore, the frequency of a functional SNP of MMP-7 (À181A4G) was found to be significantly higher in gastric cardiac carcinoma patients compared to controls in another Chinese study (Zhang et al, 2005). Particularly, genotypes with the MMP-7 À181G allele (A/G þ G/G) showed a significantly increased susceptibility for gastric cardiac carcinoma with an odds ratio of 1.96 (Zhang et al, 2005).…”

Active matrix metalloproteinase-7 is associated with invasion in buccal squamous cell carcinoma

“…15,29 MMP-7 is constitutively expressed in exocrine and mucosal epithelial cells in the skin, pancreas, liver, breast, intestine, and lung. In cancers of the colon, [30][31][32][33] esophagus, 34 stomach, [34][35][36] pancreas, 37 breast 38 and prostate, 39 increased MMP-7 expression is associated with tumor invasion, cancer progression, and poor prognosis. Two mechanisms may be responsible for the enhancement of cancer invasion and metastasis by MMP-7: direct effects of MMP-7 proteinase activity and indirect effects of MMP-7, such as activation of MMP-2 and MMP-9.…”