Tissue expression of MMP-9, TIMP-1, RECK, and miR338-3p in prostate gland: can it predict cancer?

Document Type : Original article

Authors

1 Laboratory of Medical Investigation (LIM55), Urology Department, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

2 D'Or Institute for Research and Education (IDOR), São Paulo, Brazil

3 Instituto Do Cancer Do Estado De São Paulo (ICESP), Universidade de São Paulo, São Paulo, Brazil

Abstract

Prostate cancer is the most frequent malignancy affecting men worldwide. Due to the low sensitivity and specificity of the prostate-specific antigen test and the digital rectal exam as screening modalities, several alternatives are being studied. This study aimed to evaluate the application of MMP-9 and its regulators (TIMP-1, RECK, and miR-338-3p) as diagnostic and prognostic indicators of prostate cancer. A total of 134 randomly selected patients under investigation for prostate cancer submitted to a transrectal ultrasound-guided prostate biopsy were enrolled in the study; of these, 61 were positive for the disease (cases), and 73 were negative (control group). The tissue samples were further analyzed by gene and miR-338-3p expression analysis using qRT-PCR (one randomly selected fragment of each patient).  Approximately 58% of the patients with prostate cancer presented MMP9 upregulation, while 73%, 65%, and 69% downregulated IMP-1, RECK, and miR-338-3p, respectively. MiR-338-3p was expressed at lower levels in patients with PSA concentrations exceeding 20 ng/mL (p=0.045) and abnormal DRE (p=0.006), while the RECK was more expressed in patients with abnormal DRE (p=0.01). We found that most patients with prostate cancer overexpressed MMP-9; on the other hand, most of them underexpressed TIMP-1, RECK, and miR-338-3p. MiR-338-3p presented as a possible predictor of poor prognosis. Further studies are warranted to evaluate these biomarkers as prognosis factors better.

Keywords


  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-249.
  2. Rawla P. Epidemiology of prostate cancer. World J Oncol 2019;10:63-89.
  3. Greene KL, Albertsen PC, Babaian RJ, Carter HB, Gann PH, Han M, Kuban DA, Sartor AO, Stanford JL, Zietman A, Carroll P, American Urological Association. Prostate specific antigen best practice statement: 2009 update. J Urol 2013;189 (1 Suppl):S2-S11.
  4. Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, Parnes HL, Coltman jr CA. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA 2005;294:66-70.
  5. Naji L, Randhawa H, Sohani Z, Dennis B, Lautenbach D, Kavanagh O, Bawor M, Banfield L, Profetto J. Digital rectal examination for prostate cancer screening in primary care: A systematic review and meta-analysis. Ann Fam Med 2018;16:149-154.
  6. Schoots IG, Roobol MJ, Nieboer D, Bangma CH, Steyerberg EW, Hunink MG. Magnetic resonance imaging-targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound-guided biopsy: a systematic review and meta-analysis. Eur Urol 2015;68:438-450.
  7. Miah S, Hosking-Jervis F, Connor MJ, Eldred-Evans D, Shah TT, Arya M, Barber N, Bhardwa J, Bott S, Burke D, Doherty A, Foster C, Freeman A, Hindley R, Jameson C, Karim O, Laniado M, Montgomery B, Nigam R, Punwani S, Sinclair A, Winkler M, Allen C, Ahmed HU. A multicentre analysis of the detection of clinically significant prostate cancer following transperineal image-fusion targeted and nontargeted systematic prostate biopsy in men at risk. Eur Urol Oncol 2020;3:262-269.
  8. Salimi Sartakhti J, Manshaei MH, Sadeghi M. MMP-TIMP interactions in cancer invasion: An evolutionary game-theoretical framework. J Theor Biol 2017;412:17-26.
  9. Reis ST, Viana NI, Iscaife A, Pontes-Junior J, Dip N, Antunes AA, Guimaraes VR, Santana I, Nahas WC, Srougi M, Moreira Leite KR. Loss of TIMP-1 immune expression and tumor recurrence in localized prostate cancer. Int Braz J Urol 2015;41:1088-1095.
  10. Reis ST, Leite KRM, Piovesan LF, Pontes-Junior J, Viana NI, Abe DK, Crippa A, Moura CM, Adonias SP, Srougi M, Dall'Oglio MF. Increased expression of MMP-9 and IL-8 are correlated with poor prognosis of Bladder Cancer. BMC Urol 2012;12:18.
  11. Oh J, Takahashi R, Kondo S, Mizoguchi A, Adachi E, Sasahara RM, Nishimura S, Imamura Y, Kitayama H, Alexander DB, Ide C, Horan TP, Arakawa T, Yoshida H, Nishikawa S, Itoh Y, Seiki M, Itohara S, Takahashi C, Noda M. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell. 2001;107: 789-800.
  12. Leite KR, Reis ST, Viana N, Morais DR, Moura CM, Silva IA, Pontes J, Katz B, Srougi M. Controlling RECK miR21 promotes tumor cell invasion and is related to biochemical recurrence in prostate cancer. J Cancer 2015;6:292-301.
  13. Huang XH, Chen JS, Wang Q, Chen XL, Wen L, Chen LZ, Bi J, Zhang LJ, Su Q, Zeng WT. miR-338-3p suppresses invasion of liver cancer cell by targeting smoothened. J Pathol 2011;225:463-472.
  14. Liu HT, Gao P. The roles of microRNAs related with progression and metastasis in human cancers. Tumour Biol 2016.
  15. Babichenko II, Andriukhin MI, Pulbere S, Loktev A. Immunohistochemical expression of matrix metalloproteinase-9 and inhibitor of matrix metalloproteinase-1 in prostate adenocarcinoma. Int J Clin Exp Pathol 2014;7:9090-9098.
  16. Reis ST, Pontes-Junior J, Antunes AA, de Sousa-Canavez JM, Dall'Oglio MF, Passerotti CC, Abe DK, Crippa A, Cruz JAS, Timoszczuk LMS, Srougi M, Leite KRM. MMP-9 overexpression due to TIMP-1 and RECK underexpression is associated with prognosis in prostate cancer. Int J Biol Markers 2011;26:255-261.
  17. Seubert B, Grünwald B, Kobuch J, Cui H, Schelter F, Schaten S, Siveke JT, Lim NH, Nagase H, Simonavicius N, Heikenwalder M, Reinheckel T, Sleeman JP, Janssen KP, Knolle PA, Kruger A. Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice. Hepatology 2015;61:238-248.
  18. Rabien A, Ergün B, Erbersdobler A, Jung K, Stephan C. RECK overexpression decreases invasive potential in prostate cancer cells. Prostate 2012;72:948-954.
  19. Chen R, Sheng L, Zhang HJ, Ji M, Qian WQ. miR-15b-5p facilitates the tumorigenicity by targeting RECK and predicts tumour recurrence in prostate cancer. J Cell Mol Med 2018; 22:1855-1863.
  20. Bakkar A, Alshalalfa M, Petersen LF, Abou-Ouf H, Al-Mami A, Hegazy SA, Feng F, Alhajj R, Bijian K, Jamali MA, Bismar TA. microRNA 338-3p exhibits tumor suppressor role and its down-regulation is associated with adverse clinical outcome in prostate cancer patients. Mol Biol Rep 2016;43:229-240.