Matrix Metalloproteinase-13 - A Potential Biomarker for Detection and Prognostic Assessment of Patients with Esophageal Squamous Cell Carcinoma

  • Sedighi, Maryam (Division of Human Genetics, Immunology Research Center, Avicenna Research Institute) ;
  • Aledavood, Seyed Amir (Department of Radiotherapy and Oncology, Omid Hospital, Mashhad University of Medical Sciences) ;
  • Abbaszadegan, MR (Division of Human Genetics, Immunology Research Center, Avicenna Research Institute) ;
  • Memar, Bahram (Department of Pathology, Omid Hospital, Mashhad University of Medical Sciences) ;
  • Montazer, Mehdi (Department of Pathology, Omid Hospital, Mashhad University of Medical Sciences) ;
  • Rajabian, Majid (Herbal biochemistry Department, payamnoor university- Faculty of basic science- Biology Group) ;
  • Gholamin, Mehran (Division of Human Genetics, Immunology Research Center, Avicenna Research Institute)
  • Published : 2016.06.01


Background: Matric metalloproteinase (MMP) 13 gene expression is increased in esophageal squamous cell carcinomas (ESCCs) and associated with increasing tumor invasion, lymph node involvement and decreased survival rates. Levels of the circulating enzyme may be elevated and used as a marker of tumor progression. In this study, clinical application of MMP-13 serum levels was evaluated for early detection, prediction of prognosis and survival time of ESCC patients. Materials and Methods: Serum levels of MMP13 were determined by ELISA in 66 ESCC patients prior of any treatment and 54 healthy controls for comparison with clinicopathological data through statistical analysis with Man Whitney U and Log-Rank tests. In addition, clinical value of MMP13 levels for diagnosis was evaluated by receiver operating characteristic (ROC) test. Results: The serum level of MMP-13 in patients (>250 pg/ml) was significantly higher than in the control group (<100 pg/ml) (p value=0.004). Also the results showed a significant correlation between MMP-13 serum levels with tumor stage (p value = 0.003), depth of tumor invasion (p value=0.008), involvement of lymph nodes (p value = 0.011), tumor size (p value = 0.018) and survival time. While there were no significant correlation with grade and location of tumors. ROC analysis showed that MMP-13 level is an accurate diagnostic marker especially to differentiate pre-invasive/ invasive lesions from normal controls (sensitivity and specificity: 100%). Conclusions: These findings indicate a potential clinical significance of serum MMP13 measurement for early detection and prognostic assessment in ESCC patients.


Supported by : Mashhad University of Medical Sciences


  1. Akhtar N, Rasheed Z, Ramamurthy S, et al (2010). MicroRNA-27b regulates the expression of matrix metalloproteinase 13 in human osteoarthritis chondrocytes. Arthritis Rheum, 62, 1361-71.
  2. Amalinei C, Caruntu ID, Balan RA (2007). Biology of metalloproteinases. Rom J Morphol Embryol, 48, 323-34.
  3. Clark IM, Swingler TE, Sampieri CL, et al (2008). The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol, 40, 1362-78.
  4. Colotta F, Allavena P, Sica A, et al (2009). Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis, 30, 1073-81.
  5. Cruz-Munoz W, Khokha R (2008). The role of tissue inhibitors of metalloproteinases in tumorigenesis and metastasis. Crit Rev Clin Lab Sci, 45, 291-338.
  6. Elnemr A, Yonemura Y, Bandou E, et al (2003). Expression of collagenase-3 (matrix metalloproteinase-13) in human gastric cancer. Gastric Cancer, 6, 30-8.
  7. Etoh T, Inoue H, Yoshikawa Y, et al (2000). Increased expression of collagenase-3 (MMP-13) and MT1-MMP in oesophageal cancer is related to cancer aggressiveness. Gut, 47, 50-6.
  8. Ghadimi MR, Rasouli M, Mahmoodi M, et al (2011). Prognostic factors for the survival of patients with esophageal cancer in Northern Iran. J Res Med Sci, 16, 1261-72.
  9. Gholamin M, Moaven O, Farshchian M, et al (2010). Induction of cytotoxic T lymphocytes primed with tumor RNA-loaded dendritic cells in esophageal squamous cell carcinoma: preliminary step for DC vaccine design. BMC Cancer, 10, 261.
  10. Hanahan D, Weinberg RA (2000). The hallmarks of cancer. Cell, 100, 57-70.
  11. Hsu CP, Shen GH, Ko JL (2006). Matrix metalloproteinase-13 expression is associated with bone marrow microinvolvement and prognosis in non-small cell lung cancer. Lung Cancer, 52, 349-57.
  12. Jiao XL, Chen D, Wang JG, et al (2014). Clinical significance of serum matrix metalloproteinase-13 levels in patients with esophageal squamous cell carcinoma (ESCC). Eur Rev Med Pharmacol Sci, 18, 509-15.
  13. Johansson N, Vaalamo M, Grenman S, et al (1999). Collagenase-3 (MMP-13) is expressed by tumor cells in invasive vulvar squamous cell carcinomas. Am J Pathol, 154, 469-80.
  14. Leeman MF, Curran S, Murray GI (2002). The structure, regulation, and function of human matrix metalloproteinase-13. Crit Rev Biochem Mol Biol, 37, 149-66.
  15. Mannello F, Tonti GA, Bagnara GP, et al (2006). Role and function of matrix metalloproteinases in the differentiation and biological characterization of mesenchymal stem cells. Stem Cells, 24, 475-81.
  16. Nikkola J, Vihinen P, Vuoristo MS, et al (2005). High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. Clin Cancer Res, 11, 5158-66.
  17. Rice TW, Rusch VW, Ishwaran H, et al (2010). Cancer of the esophagus and esophagogastric junction: data-driven staging for the seventh edition of the american joint committee on cancer/international union against cancer cancer staging manuals. Cancer, 116, 3763-73.
  18. Sbardella D, Fasciglione GF, Gioia M, et al (2012). Human matrix metalloproteinases: an ubiquitarian class of enzymes involved in several pathological processes. Mol Aspects Med, 33, 119-208.
  19. Taziki MH, Rajaee S, Behnampour N, et al (2011). Esophageal cancer: 5-year survival rate at south-east of Caspian sea of northern Iran. J Cancer Res Ther, 7, 135-7.
  20. Vazquez-Sequeiros E, Wiersema MJ, Clain JE, et al (2003). Impact of lymph node staging on therapy of esophageal carcinoma. Gastroenterology, 125, 1626-35.
  21. Yan D, Dai H, Liu JW Serum levels of MMP-11 correlate with clinical outcome in Chinese patients with advanced gastric adenocarcinoma. BMC Cancer, 11, 151.
  22. Yoon SO, Park SJ, Yun CH, et al (2003). Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J Biochem Mol Biol, 36, 128-37.
  23. Zhang B, Cao X, Liu Y, et al (2008). Tumor-derived matrix metalloproteinase-13 (MMP-13) correlates with poor prognoses of invasive breast cancer. BMC Cancer, 8, 83.
  24. Chang HJ, Yang MJ, Yang YH, et al (2009). MMP13 is potentially a new tumor marker for breast cancer diagnosis. Oncol Rep, 22, 1119-27.