An Overview of Matrix Metalloproteinase 9 Polymorphism and Gastric Cancer Risk

  • Verma, Sugreev (Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology) ;
  • Kesh, Kousik (Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology) ;
  • Gupta, Arnab (Saroj Gupta Cancer Centre and Research Institute) ;
  • Swarnakar, Snehasikta (Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology)
  • Published : 2015.12.03


Matrix metalloproteinase (MMP) 9, a key member of multifunctional family of zinc dependent endopeptidases has been found to be upregulated during inflammation and in some cancers. MMPs cleave extracellular matrix (ECM) proteins and play critical roles in cellular apoptosis, angiogenesis, tumor growth and metastasis. Several genetic polymorphisms have been identified that show allele specific effects on MMP9 regulation and are associated with gastric cancer, the fourth most common malignancy in the world. Besides Helicobacter pylori infection, genetic predisposition is another documented risk factor for gastric carcinoma. The single nucleotide polymorphism (SNP) at position -1562C/T of MMP9 results in the modulation for binding of transcription factors to the MMP9 gene promoter and thereby causes differences in protein expression and enzymatic activity. MMP9 transcriptional regulation during gastric cancer development remains poorly known although several studies have demonstrated associations between MMP9 -1562 C/T polymorphism with different diseases. Knowledge on mechanisms of MMP9 upregulation during gastric cancer may provide new paradigm in diagnostics and therapeutics.


Gastric cancer;matrix metalloproteinase 9;single nucleotide polymorphism;case control study


  1. Langers AM, Verspaget HW, Hommes DW, et al (2011). Singlenucleotide polymorphisms of matrix metalloproteinases and their inhibitors in gastrointestinal cancer. World J Gastrointest Oncol, 3, 79-98.
  2. Lee SH, Han SK, Shim YS, et al (2009). Effect of matrix metalloproteinase-9 -1562C/T gene polymorphism on manifestations of pulmonary tuberculosis. Tuberculosis (Edinb), 89, 68-70.
  3. Lee TY, Yu CC, Wu CC, et al (2013). MMP-9 -1562 Promoter Polymorphism Associated with Gastric Cancer Risk in Females. Hepatogastroenterology, 60.
  4. Libermann TA, Zerbini LF (2006). Targeting transcription factors for cancer gene therapy. Curr Gene Ther, 6, 17-33.
  5. Maeda S, Haneda M, Guo B, et al (2001). Dinucleotide repeat polymorphism of matrix metalloproteinase-9 gene is associated with diabetic nephropathy. Kidney Int, 60, 1428-34.
  6. Matsumura S, Oue N, Nakayama H, et al (2005). A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer. J Cancer Res Clin Oncol, 131, 19-25.
  7. McDonnell S, Matrisian LM (1990). Stromelysin in tumor progression and metastasis. Cancer Metastasis Rev, 9, 305-19.
  8. Murthy NS, Chaudhry K, Rath GK (2008). Burden of cancer and projections for 2016, Indian scenario: gaps in the availability of radiotherapy treatment facilities. Asian Pac J Cancer Prev, 9, 671-7.
  9. Nakayama T, Ito M, Ohtsuru A, et al (1996). Expression of the Ets-1 proto-oncogene in human gastric carcinoma: correlation with tumor invasion. Am J Pathol, 149, 1931-9.
  10. Nomura H, Sato H, Seiki M, et al (1995). Expression of membrane-type matrix metalloproteinase in human gastric carcinomas. Cancer Res, 55, 3263-6.
  11. Ozalp S, Tanir HM, Yalcin OT, et al (2003). Prognostic value of matrix metalloproteinase-9 (gelatinase-B) expression in epithelial ovarian tumors. Eur J Gynaecol Oncol, 24, 417-20.
  12. Pinto LA, Depner M, Klopp N, et al (2010). MMP-9 gene variants increase the risk for non-atopic asthma in children. Respir Res, 11, 23.
  13. Sakata K, Satoh M, Someya M, et al (2004). Expression of matrix metalloproteinase 9 is a prognostic factor in patients with non-Hodgkin lymphoma. Cancer, 100, 356-65.
  14. Sentani K, Oue N, Sakamoto N, et al (2008). Gene expression profiling with microarray and SAGE identifies PLUNC as a marker for hepatoid adenocarcinoma of the stomach. Mod Pathol, 21, 464-75.
  15. Shimajiri S, Arima N, Tanimoto A, et al (1999). Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene. FEBS Lett, 455, 70-4.
  16. Sier CF, Kubben FJ, Ganesh S, et al (1996). Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma. Br J Cancer, 74, 413-7.
  17. Sternlicht MD, Werb Z (2001). How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol, 17, 463-516.
  18. Swarnakar S, Ganguly K, Kundu P, et al (2005). Curcumin regulates expression and activity of matrix metalloproteinases 9 and 2 during prevention and healing of indomethacininduced gastric ulcer. J Biol Chem, 280, 9409-15.
  19. Tan SY, Wang JY, Shen L, et al (2007). Relationship between preoperative staging by endoscopic ultrasonography and MMP-9 expression in gastric carcinoma. World J Gastroenterol, 13, 2108-12.
  20. Tang Y, Zhu J, Chen L, et al (2008). Associations of matrix metalloproteinase-9 protein polymorphisms with lymph node metastasis but not invasion of gastric cancer. Clin Cancer Res, 14, 2870-7.
  21. Tanioka Y, Yoshida T, Yagawa T, et al (2003). Matrix metalloproteinase-7 and matrix metalloproteinase-9 are associated with unfavourable prognosis in superficial oesophageal cancer. Br J Cancer, 89, 2116-21.
  22. Venkateshwari A, Sri Manjari K, Krishnaveni D, et al (2011). Role of Plasma MMP 9 levels in the pathogenesis of chronic pancreatitis. Indian J Clin Biochem, 26, 136-9.
  23. Woo M, Park K, Nam J, et al (2007). Clinical implications of matrix metalloproteinase-1, -3, -7, -9, -12, and plasminogen activator inhibitor-1 gene polymorphisms in colorectal cancer. J Gastroenterol Hepatol, 22, 1064-70.
  24. Wu CW, Chi CW, Lin WC (2002). Gastric cancer: prognostic and diagnostic advances. Expert Rev Mol Med, 4, 1-12.
  25. Xing LL, Wang ZN, Jiang L, et al (2007). Matrix metalloproteinase-9-1562C>T polymorphism may increase the risk of lymphatic metastasis of colorectal cancer. World J Gastroenterol, 13, 4626-9.
  26. Ye S, Eriksson P, Hamsten A, et al (1996). Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem, 271, 13055-60.
  27. Zhang B, Ye S, Herrmann SM, et al (1999). Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation, 99, 1788-94.
  28. Zhang J, Jin X, Fang S, et al (2004a). The functional SNP in the matrix metalloproteinase-3 promoter modifies susceptibility and lymphatic metastasis in esophageal squamous cell carcinoma but not in gastric cardiac adenocarcinoma. Carcinogenesis, 25, 2519-24.
  29. Zhang QW, Liu L, Chen R, et al (2012). Matrix metalloproteinase-9 as a prognostic factor in gastric cancer: a meta-analysis. Asian Pac J Cancer Prev, 13, 2903-8.
  30. Baker EA, Leaper DJ (2003). The plasminogen activator and matrix metalloproteinase systems in colorectal cancer: relationship to tumour pathology. Eur J Cancer, 39, 981-8.
  31. Battle A, Khan Z, Wang SH, et al (2015). Genomic variation. Impact of regulatory variation from RNA to protein. Science, 347, 664-7.
  32. Behrens P, Rothe M, Wellmann A, et al (2001). The Ets-1 transcription factor is up-regulated together with MMP 1 and MMP 9 in the stroma of pre-invasive breast cancer. J Pathol, 194, 43-50.
  33. Choi IS, Wu TT (2005). Epigenetic alterations in gastric carcinogenesis. Cell Res, 15, 247-54.
  34. Crew KD, Neugut AI (2006). Epidemiology of gastric cancer. World J Gastroenterol, 12, 354-62.
  35. Dikshit RP, Mathur G, Mhatre S, et al (2011). Epidemiological review of gastric cancer in India. Indian J Med Paediatr Oncol, 32, 3-11.
  36. Fanjul-Fernandez M, Folgueras AR, Cabrera S, et al (2010). Matrix metalloproteinases: Evolution, gene regulation and functional analysis in mouse models. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1803, 3-19.
  37. Ferlay J, Shin HR, Bray F, et al (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 127, 2893-917.
  38. Forget MA, Desrosiers RR, Beliveau R (1999). Physiological roles of matrix metalloproteinases: implications for tumor growth and metastasis. Can J Physiol Pharmacol, 77, 465-80.
  39. Fox JG, Wang TC (2007). Inflammation, atrophy, and gastric cancer. J Clin Invest, 117, 60-9.
  40. Ghilardi G, Biondi ML, Mangoni J, et al (2001). Matrix metalloproteinase-1 promoter polymorphism 1G/2G is correlated with colorectal cancer invasiveness. Clin Cancer Res, 7, 2344-6.
  41. Gum R, Lengyel E, Juarez J, et al (1996). Stimulation of 92-kDa gelatinase B promoter activity by ras is mitogen-activated protein kinase kinase 1-independent and requires multiple transcription factor binding sites including closely spaced PEA3/ets and AP-1 sequences. J Biol Chem, 271, 10672-80.
  42. Hannenhalli S (2008). Eukaryotic transcription factor binding sites--modeling and integrative search methods. Bioinformatics, 24, 1325-31.
  43. Hellmig S, Ott S, Rosenstiel P, et al (2006). Genetic variants in matrix metalloproteinase genes are associated with development of gastric ulcer in H. Pylori infection. Am J Gastroenterol, 101, 29-35.
  44. Hirakawa S, Lange EM, Colicigno CJ, et al (2003). Evaluation of genetic variation and association in the matrix metalloproteinase 9 (MMP9) gene in ESRD patients. Am J Kidney Dis, 42, 133-42.
  45. Honda M, Mori M, Ueo H, et al (1996). Matrix metalloproteinase-7 expression in gastric carcinoma. Gut, 39, 444-8.
  46. Hu Z, Huo X, Lu D, et al (2005). Functional polymorphisms of matrix metalloproteinase-9 are associated with risk of occurrence and metastasis of lung cancer. Clin Cancer Res, 11, 5433-9.
  47. Inoue T, Yashiro M, Nishimura S, et al (1999). Matrix metalloproteinase-1 expression is a prognostic factor for patients with advanced gastric cancer. Int J Mol Med, 4, 73-7.
  48. Inuzuka K, Ogata Y, Nagase H, et al (2000). Significance of coexpression of urokinase-type plasminogen activator, and matrix metalloproteinase 3 (stromelysin) and 9 (gelatinase B) in colorectal carcinoma. J Surg Res, 93, 211-8.
  49. Joos L, He JQ, Shepherdson MB, et al (2002). The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function. Hum Mol Genet, 11, 569-76.
  50. Kallakury BV, Karikehalli S, Haholu A, et al (2001). Increased expression of matrix metalloproteinases 2 and 9 and tissue inhibitors of metalloproteinases 1 and 2 correlate with poor prognostic variables in renal cell carcinoma. Clin Cancer Res, 7, 3113-9.
  51. Kanamori Y, Matsushima M, Minaguchi T, et al (1999). Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region. Cancer Res, 59, 4225-7.
  52. Kim JH, Pyun JA, Lee KJ, et al (2011). [Study on association between single nucleotide polymorphisms of MMP7, MMP8, MMP9 genes and development of gastric cancer and lymph node metastasis]. Korean J Gastroenterol, 58, 245-51.
  53. Kohn EC, Liotta LA (1995). Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res, 55, 1856-62.
  54. Kubben FJ, Sier CF, Meijer MJ, et al (2006). Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer. Br J Cancer, 95, 744-51.
  55. Kundu P, Mukhopadhyay AK, Patra R, et al (2006). Cag pathogenicity island-independent up-regulation of matrix metalloproteinases-9 and -2 secretion and expression in mice by Helicobacter pylori infection. J Biol Chem, 281, 34651-62.
  56. Zhang S, Li L, Lin JY, et al (2003). Imbalance between expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in invasiveness and metastasis of human gastric carcinoma. World J Gastroenterol, 9, 899-904.
  57. Zhang XM, Miao XP, Xiong P, et al (2004b). [Association of functional polymorphisms in matrix metalloproteinase-2 (MMP-2) and MMP-9 genes with risk of gastric cancer in a Chinese population]. Ai Zheng, 23, 1233-7.

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