The Role of the Matrix Metalloproteinase-9 Gene in Tumor Development and Metastasis: A Narrative Review

Abstract

Matrix metalloproteinase-9 (MMP-9) is one of the widely studied enzymes of the extracellular matrix which can degrade various matrix biomolecules. The gene coding for this enzyme has been found to be associated with various multifactorial diseases, including cancer. More specifically, the expression of MMP-9 and polymorphisms of its gene have been found to be correlated with the formation and the invasiveness of different types of cancer. Hence, the latter gene can potentially be used both as a clinical genetic marker and a possible target in anticancer therapy. The present minireview explores the role of the MMP-9 gene in the process of tumor formation, growth, and metastasis and presents an overview of the polymorphisms of the gene associated with cancer as well as its regulation mechanisms, to provide an insight into the potential clinical applications. Nevertheless, further clinical trials and research are still required to reach more valuable conclusions for the clinical implications of the recent findings.

Keywords

matrix metalloproteinases / MMP-9 / carcinogenesis / metastasis / oncogenes

References

[1] Cui N, Hu M, Khalil RA. Biochemical and biological attributes of matrix metalloproteinases. Prog Mol Biol Transl Sci 2017; 147:1-73

[2] Vandooren J, Van den Steen PE, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Crit Rev Biochem Mol Biol 2013;48(03):222-272

[3] Xu D, Suenaga N, Edelmann MJ, Fridman R, Muschel RJ, Kessler BM. Novel MMP-9 substrates in cancer cells revealed by a labelfree quantitative proteomics approach.Mol Cell Proteomics 2008; 7(11):2215-2228

[4] Hangauer DG, Monzingo AF, Matthews BW. An interactive computer graphics study of thermolysin-catalyzed peptide cleavage and inhibition by N-carboxymethyl dipeptides. Biochemistry 1984;23(24):5730-5741

[5] Zhang J, Wang S, He Y, Yao B, Zhang Y. Regulation of matrix metalloproteinases 2 and 9 in corneal neovascularization. Chem Biol Drug Des 2020;95(05):485-492

[6] Lelongt B, Legallicier B, Piedagnel R, Ronco PM. Do matrix metalloproteinasesMMP- 2 andMMP-9 (gelatinases) play a role in renal development, physiology and glomerular diseases? Curr Opin Nephrol Hypertens 2001;10(01):7-12

[7] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022;72(01):7-33

[8] Walker C, Mojares E, Del Río Hernández A. Role of extracellular matrix in development and cancer progression. Int JMol Sci 2018; 19(10):3028

[9] Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 2012;196(04):395-406

[10] Sauer TJ, Samei E, Bejan A. Cell and extracellular matrix growth theory and its implications for tumorigenesis. Biosystems 2021; 201:104331

[11] Gerarduzzi C, Hartmann U, Leask A, Drobetsky E. The matrix revolution: matricellular proteins and restructuring of the cancer microenvironment. Cancer Res 2020;80(13): 2705-2717

[12] Dofara SG, Chang SL, Diorio C. Gene polymorphisms and circulating levels of MMP-2 and MMP-9: a review of their role in breast cancer risk. Anticancer Res 2020;40(07):3619-3631

[13] Zhang C, Li C, Zhu M, et al. Meta-analysis of MMP2, MMP3, and MMP9 promoter polymorphisms and head and neck cancer risk. PLoS One 2013;8(04):e62023

[14] Elgundi Z, Papanicolaou M, Major G, et al. Cancer metastasis: the role of the extracellular matrix and the heparan sulfate proteoglycan perlecan. Front Oncol 2020;9:1482

[15] Patil R, Mahajan A, Pradeep GL, Prakash N, Patil S, Khan SM. Expression of matrix metalloproteinase-9 in histological grades of oral squamous cell carcinoma: an immunohistochemical study. J Oral Maxillofac Pathol 2021;25(02):239-246

[16] Liu JF, Chen PC, Chang TM, Hou CH. Thrombospondin-2 stimulates MMP-9 production and promotes osteosarcoma metastasis via the PLC, PKC, c-Src and NF-κB activation. J Cell Mol Med 2020;24(21):12826-12839

[17] Yao Z, Yuan T, Wang H, et al. MMP-2 together with MMP-9 overexpression correlated with lymph node metastasis and poor prognosis in early gastric carcinoma. Tumour Biol 2017;39(06):1010428317700411

[18] Huang H. Matrix metalloproteinase-9 (MMP-9) as a cancer biomarker and MMP-9 biosensors: recent advances. Sensors (Basel) 2018;18(10):3249

[19] Yabluchanskiy A, Ma Y, Iyer RP, Hall ME, Lindsey ML. Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. Physiology (Bethesda) 2013;28(06):391-403

[20] Greenlee KJ, Corry DB, Engler DA, et al. Proteomic identification of in vivo substrates for matrix metalloproteinases 2 and 9 reveals a mechanism for resolution of inflammation. J Immunol 2006;177(10):7312-7321

[21] Khandia R,Munjal A. Interplay between inflammation and cancer. Adv Protein Chem Struct Biol 2020;119:199-245

[22] Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010;141(01): 52-67

[23] Schönbeck U, Mach F, Libby P. Generation of biologically active IL- 1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. J Immunol 1998;161(07): 3340-3346

[24] Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase- 9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 2000;14(02):163-176

[25] Bierie B, Moses HL. Transforming growth factor beta (TGF-beta) and inflammation in cancer. Cytokine Growth Factor Rev 2010;21(01):49-59

[26] Quintero-Fabián S, Arreola R, Becerril-Villanueva E, et al. Role of matrix metalloproteinases in angiogenesis and cancer. Front Oncol 2019;9:1370

[27] Kai F, Laklai H,Weaver VM. Force matters: biomechanical regulation of cell invasion and migration in disease. Trends Cell Biol 2016;26(07):486-497

[28] Tanjore H, Kalluri R. The role of type IV collagen and basement membranes in cancer progression and metastasis. Am J Pathol 2006;168(03):715-717

[29] Zeng Z-S, Cohen AM, Guillem JG. Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis. Carcinogenesis 1999;20(05): 749-755

[30] Farina AR, Mackay AR. Gelatinase B/MMP-9 in tumour pathogenesis and progression. Cancers (Basel) 2014;6(01):240-296

[31] Kim YH, Kwon HJ, Kim DS. Matrix metalloproteinase 9 (MMP- 9)-dependent processing of βig-h3 protein regulates cell migration, invasion, and adhesion. J Biol Chem 2012;287(46): 38957-38969

[32] Deryugina EI, Quigley JP. Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature. Matrix Biol 2015;44-46:94-112

[33] Clavel J. Progress in the epidemiological understanding of geneenvironment interactions in major diseases: cancer. C R Biol 2007;330(04):306-317

[34] Zhang X, Jin G, Li J, Zhang L. Association between four MMP-9 polymorphisms and breast cancer risk: a meta-analysis. Med Sci Monit 2015;21:1115-1123

[35] Xu T, Zhang S, Qiu D, Li X, Fan Y. Association between matrix metalloproteinase 9 polymorphisms and breast cancer risk: an updated meta-analysis and trial sequential analysis. Gene 2020; 759:144972

[36] Pençe S, Özbek E, Ozan Tiryakioğlu N, Ersoy Tunali N, Pençe HH, Tunali H. rs3918242 variant genotype frequency and increased TIMP-2 and MMP-9 expression are positively correlated with cancer invasion in urinary bladder cancer. Cell Mol Biol 2017; 63(09):46-52

[37] Hu C, Weng F, Li L, et al. Association between MMP-9 -1562 C/T polymorphism and susceptibility to digestive cancers: a metaanalysis. Gene 2018;673:88-94

[38] Wu MH, Tzeng HE, Wu CN, et al. Association of matrix metalloproteinase- 9 rs3918242 promoter genotypes with colorectal cancer risk. Anticancer Res 2019;39(12):6523-6529

[39] Fu CK, Chang WS, Tsai CW, et al. The association of MMP9 promoter rs3918242 genotype with gastric cancer. Anticancer Res 2021;41(07):3309-3315

[40] Hu C, Wang J, Xu Y, et al. Current evidence on the relationship between five polymorphisms in the matrix metalloproteinases (MMP) gene and lung cancer risk: a meta-analysis.Gene 2013;517(01):65-71

[41] Lin CM, Zeng YL, Xiao M, et al. The relationship between MMP-2 -1306C>T and MMP-9 -1562C>T polymorphisms and the risk and prognosis of T-Cell acute lymphoblastic leukemia in a Chinese population: a case-control study. Cell Physiol Biochem 2017;42(04):1458-1468

[42] Cotignola J, Reva B, Mitra N, et al. Matrix metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma. BMC Med Genet 2007;8:10

[43] Vairaktaris E, Vassiliou S, Nkenke E, et al. A metalloproteinase-9 polymorphism which affects its expression is associated with increased risk for oral squamous cell carcinoma. Eur J Surg Oncol 2008;34(04):450-455

[44] Pereira AC, Dias do Carmo E, Dias da Silva MA, Blumer Rosa LE. Matrix metalloproteinase gene polymorphisms and oral cancer. J Clin Exp Dent 2012;4(05):e297-e301

[45] Zhu XM, Sun WF. Association between matrix metalloproteinases polymorphisms and ovarian cancer risk: a meta-analysis and systematic review. PLoS One 2017;12(09):e0185456

[46] Zhou H, Zhu X. Association between matrix-metalloproteinase polymorphisms and prostate cancer risk: a meta-analysis and systematic review. Cancer Manag Res 2018;10:5247-5259

[47] Awakura Y, Ito N, Nakamura E, et al. Matrix metalloproteinase-9 polymorphisms and renal cell carcinoma in a Japanese population. Cancer Lett 2006;241(01):59-63

[48] Dobrescu R, Schipor S, Manda D, Caragheorgheopol A, Badiu C. Matrix metalloproteinase-9 (MMP-9) promoter -1562C/T functional polymorphism is associated with an increased risk to develop micropapillary thyroid carcinoma. Cancer Biomark 2022;34(04):555-562

[49] Rončević J, Janković Miljuš J, Išić Denčić T, et al. Predictive significance of two MMP-9 promoter polymorphisms and acetylated c-jun transcription factor for papillary thyroid carcinoma advancement. Diagnostics (Basel) 2022;12(08):1953

[50] Skibola CF, Bracci PM, Halperin E, et al. Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphoma. PLoS One 2008;3(07):e2816

[51] Buttacavoli M, Di Cara G, Roz E, Pucci-Minafra I, Feo S, Cancemi P. Integrated multi-omics investigations of metalloproteinases in colon cancer: focus on MMP2 and MMP9. Int J Mol Sci 2021;22(22):12389

[52] Blankenberg S, Rupprecht HJ, Poirier O, et al; AtheroGene Investigators. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 2003;107(12):1579-1585

[53] Augoff K, Hryniewicz-Jankowska A, Tabola R, Stach K. MMP9: a tough target for targeted therapy for cancer. Cancers (Basel) 2022; 14(07):1847

[54] Cheng CY, Kuo CT, Lin CC, Hsieh HL, Yang CM. IL-1beta induces expression of matrixmetalloproteinase-9 and cell migration via a c-Src-dependent, growth factor receptor transactivation in A549 cells. Br J Pharmacol 2010;160(07):1595-1610

[55] Cheng G,Wei L, Xiurong W, Xiangzhen L, Shiguang Z, Songbin F. IL- 17 stimulates migration of carotid artery vascular smoothmuscle cells in an MMP-9 dependent manner via p38MAPK and ERK1/2- dependent NF-kappaB and AP-1 activation. Cell Mol Neurobiol 2009;29(08):1161-1168

[56] Han YP, Tuan TL, Hughes M, Wu H, Garner WL. Transforming growth factor-beta - and tumor necrosis factor-alpha -mediated induction and proteolytic activation of MMP-9 in human skin. J Biol Chem 2001;276(25):22341-22350

[57] Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family of protein kinaseswith diverse biological functions.Microbiol Mol Biol Rev 2004;68(02):320-344

[58] Lee KW, Kim MS, Kang NJ, et al. H-Ras selectively up-regulates MMP-9 and COX-2 through activation of ERK1/2 and NF-kappaB: an implication for invasive phenotype in rat liver epithelial cells. Int J Cancer 2006;119(08):1767-1775

[59] Bera A, Zhao S, Cao L, Chiao PJ, Freeman JW. Oncogenic K-Ras and loss of Smad4mediate invasion by activating an EGFR/NF-κB Axis that induces expression of MMP9 and uPA in human pancreas progenitor cells. PLoS One 2013;8(12):e82282

[60] Klassen LMB, Chequin A, Manica GCM, et al. MMP9 gene expression regulation by intragenic epigenetic modifications in breast cancer. Gene 2018;642:461-466

[61] Petrusenko NA, Gvaldin DY, Yurchenko DY, Kuznetsov SA, Burtsev DV, Kit OI. Methylation of MMP2 and MMP9 in patients with localized and generalized forms of Ewing’s sarcoma. J Clin Oncol 2021;39(15, suppl):e23503-e23503

[62] Chicoine E, Estève P-O, Robledo O, Van Themsche C, Potworowski EF, St-Pierre Y. Evidence for the role of promoter methylation in the regulation of MMP-9 gene expression. Biochem Biophys Res Commun 2002;297(04):765-772

[63] Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics 2009;1(02):239-259

[64] Vandenbroucke RE, Libert C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov 2014; 13(12):904-927

[65] Park J-H, Cho YY, Yoon SW, Park B. Suppression ofMMP-9 and FAK expression by pomolic acid via blocking of NF-κB/ERK/mTOR signaling pathways in growth factor-stimulated human breast cancer cells. Int J Oncol 2016;49(03):1230-1240

[66] Xia Y, Lian S, Khoi PN, et al. Chrysin inhibits tumor promoterinduced MMP-9 expression by blocking AP-1 via suppression of ERK and JNK pathways in gastric cancer cells. PLoS One 2015;10(04):e0124007

[67] Hong O-Y, Jang H-Y, Lee Y-R, Jung SH, Youn HJ, Kim J-S. Inhibition of cell invasion and migration by targeting matrix metalloproteinase- 9 expression via sirtuin 6 silencing in human breast cancer cells. Sci Rep 2022;12(01):12125

[68] Zhang Q, Fu Q, Bai X, Liang T. Molecular profiling-based precision medicine in cancer: a review of current evidence and challenges. Front Oncol 2020;10:532403

[69] Ooki A, Satoh T, Muro K, et al. A phase 1b study of andecaliximab in combination with S-1 plus platinum in Japanese patients with gastric adenocarcinoma. Sci Rep 2022;12(01):11007

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