Activities and polymorphisms of MMP-2 and MMP-9, smoking, diabetes and risk of prostate cancer

Mol Biol Rep. 2020 Dec;47(12):9373-9383. doi: 10.1007/s11033-020-05968-5. Epub 2020 Nov 9.

Abstract

Matrix metalloproteinases (MMPs) are a group of zinc dependent enzymes that are involved in tumor cell invasion and metastasis. The role of MMP-2 and -9 genetic polymorphism in different malignancies has been the subject of numerous studies. The present research has attempted to discover any positive correlation between MMP-2 and MMP-9 SNPs and prostate cancer (PCa) in patients with a history of either diabetes or smoking habits. 112 PCa-patients and 150 unrelated healthy-controls that matched for age and sex were selected for present case-control study. MMP-2 -1575G/A and MMP-9 -1562 C/T polymorphisms detected by PCR-RFLP, serum tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), testosterone, prostate-specific antigen (PSA), free-prostate-specific-antigen (fPSA), and fPSA/PSA levels were detected by ELISA and enzyme assay, respectively. MMP-2 and MMP-9 activities were measured by gelatin-zymography. Covariates were considered as age, status of cigarette smoking, and a possible history of diabetes mellitus (DM). The frequency of -1575 MMP-2 A/A + A/G and -1562 MMP-9 C/T + T/T genotypes were higher in PCa-patients with DM (74.3%,p = 0.003) and with smoking habits (72.5%,p = 0.005). These genotypes were associated with the increased risk of prostate cancer in smokers (3.52-folds) and in individuals with history of DM (4.34-folds). A significant positive association was found between level of TIMPs (TIMP -1 and TIMP-2) and BMI in PCa-patients and also between testosterone levels and MMP-9 activity in healthy control subjects. For the first time, this study demonstrated that activities of MMP-2 -1575G/A and MMP-9 -1562C/T variants in association with smoking and diabetes are considered significant risk factors for PCa.

Keywords: Diabetes; Matrix metalloproteinase (MMP); Prostate cancer; Prostate-specific antigen and testosterone; Tissue inhibitors of metalloproteinases (TIMPs).

MeSH terms

  • Adult
  • Case-Control Studies
  • Comorbidity
  • Diabetes Mellitus / epidemiology*
  • Genotype
  • Humans
  • Iran / epidemiology
  • Male
  • Matrix Metalloproteinase 2 / blood
  • Matrix Metalloproteinase 2 / genetics*
  • Matrix Metalloproteinase 9 / blood
  • Matrix Metalloproteinase 9 / genetics*
  • Middle Aged
  • Polymorphism, Genetic*
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms / blood
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / epidemiology*
  • Prostatic Neoplasms / genetics*
  • Risk Factors
  • Smoking / epidemiology*
  • Testosterone / blood
  • Tissue Inhibitor of Metalloproteinase-1 / blood
  • Tissue Inhibitor of Metalloproteinase-2 / blood
  • Young Adult

Substances

  • TIMP1 protein, human
  • TIMP2 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-2
  • Testosterone
  • Prostate-Specific Antigen
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • MMP9 protein, human
  • Matrix Metalloproteinase 9