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.

 

MissingLinkText

Keywords

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

Introduction

Matrix metalloproteinases are a group of enzymes that can degrade various proteins and protein derivatives found in the extracellular matrix (ECM).[1] One of the widely studied enzymes of this family is matrix metalloproteinase-9 (MMP-9), which is capable of degrading type IV collagen, a basic structure of the ECM, as well as other substrates such as angiotensin II and plasminogen which are not ECM proteins.[2] [3] The MMP-9 gene which codes for the MMP-9 enzyme is found in the genetic location 20q13.12 and has been widely studied in different hereditary and multifactorial diseases, including renal and ophthalmic disorders.[4] [5] [6]

With cancer remaining a leading cause of mortality despite the novel discoveries in the field of oncology, it is necessary to study the molecular biology of cancer in more depth with the hope of discovering information which can assist the diagnosis and treatment of the disease.[7] One of the major factors that impact the development, progression, and therapeutic procedure of solid carcinomas is the tumor microenvironment, which includes the ECM and its proteins.[8] [9] On the contrary, several research has indicated that the ECM and the enzymes which assist its formation and degradation, such as matrix metalloproteinases, play a significant role in the process of oncogenesis and indeed genetic mutations in them can be a risk factor for higher predisposition to many types of cancer.[10] [11] [12] [13] With this rationale, the gene coding for MMP-9 can potentially be studied as a genetic marker of cancer as well as a possible target for cancer prevention and early-stage therapy. Moreover, it is known that for a solid tumor to migrate, it must first invade the ECM, and therefore, its enzymes are a major factor that can influence the metastatic progression of carcinomas.[14] More specifically, several studies have validated that the expression of MMP-9 is associated with a higher risk of metastasis and a lower survival expectancy in different types of cancer.[15] [16] [17]

Hence, MMP-9 is indeed a significant gene in different malignant neoplastic diseases and its multifactorial role can provide more insights into diagnostics and therapeutics in the field of medical oncology. Given that the evidence on the role of the MMP-9 gene in cancer is scattered in different research articles, the present narrative review aims to provide an overview of the available evidence, including its role in carcinogenesis and tumor migration, the polymorphisms of the gene associated with cancer, as well as its clinical significance.

 

MissingLinkText

The Role of Matrix Metalloproteinase-9 in Carcinogenesis and Metastasis

Matrix Metalloproteinase-9 as Carcinogen and Prosurvival Protein in Cancer

Due to its wide range of substrates, MMP-9 can interfere with various biological mechanisms of the organism which can subsequently trigger the process of tumorigenesis directly or indirectly.[18] To begin with, MMP-9 can activate different proteins involved in the inflammatory pathways and thus act as a proinflammation factor.[19] [20] Chronic inflammation is known to be a major mechanism which prompts tumorigenesis, and in fact, inflammatory cytokines and related cells are essential components of the tumor microenvironment.[21] Simultaneously, MMP-9 is known to cleave and activate tumor growth factors and trigger signal transduction pathways which inhibit cell apoptosis and induce increased proliferation rates.[22] A study by Schönbeck et al demonstrated that MMP-9 can cleave and, in turn, activate interleukin 1β (IL-1β) which is an inflammatory cytokine involved in many processes of inflammation.[23] Moreover, it has also been shown that MMP-9 can activate transforming growth factor-β (TGF-β) through proteolysis, and it is known that TGF-β is an inflammatory molecule that specifically acts as a bridge between inflammation and cancer.[24] [25]

On the contrary, MMP-9 is known to activate the vascular endothelial growth factor (VEGF) protein family and thereby promote angiogenesis in tumors.[26] In this manner, it assists the survival of malignant cells. Overall, MMP-9 can act as a procarcinogenic and pro-survival enzyme.

 

MissingLinkText

Matrix Metalloproteinase-9 and Metastasis

In the process of metastasis, one of the major barriers to malignant cell migration is the ECM, involved both in the process of tissue invasion and intravasation into the blood or lymph.[27] In this manner, MMP-9 due to its degrative nature in the ECM can assist tumors overcome this barrier. Specifically, the ability of MMP-9 to proteolyze type IV collagen in the basal lamina of tumors can alter the structure of the ECM and ease the invasion process.[28] [29] Furthermore, MMP-9 can degrade the adhesive proteins on the surface of malignant cells responsible for cell-to-cell adhesions as well as the proteins which adhere cells to the ECM.[18] [30] [31] Thus, cells can be released more easily from the tumor tissue and metastasize. It is also worth mentioning that the connective tissues of blood and lymph vessels are rich in proteins, including type IV collagen and elastin, that can be degraded by MMP-9, and in this manner, the enzyme can assist the intravasation of cancerous cells.[32] On the contrary, as MMP-9 is an enzyme which can assist angiogenesis and activate VEGF in cancerous tissues, it can help support metastasis as more blood vessels are created adjacent to the tumor, and hence, malignant cells can have easier access to the bloodstream.[26] All potential mechanisms of action of the MMP-9 enzyme in tumor migration have been synopsized graphically in [Fig. 1].

Fig. 1 Potential prometastatic effects of MMP-9.

 

MissingLinkText

 

MissingLinkText

Polymorphisms of the Matrix Metalloproteinase-9 Gene in Cancer

With cancer being a multifactorial disease, polymorphisms in different genes have been reported to highly increase the risk of tumorigenesis and poor prognosis.[33] Indeed, genetic polymorphisms in the MMP-9 gene have been found to be correlated with a higher risk of carcinogenesis and susceptibility to neoplastic diseases. In [Table 1], the polymorphisms of the MMP-9 that have been shown to be correlated to oncogenesis in different types of cancer have been summarized.

Table 1 Polymorphisms of the MMP-9 gene correlated with higher tumorigenesis and metastasis risk

Type of cancer	Polymorphism	Genetic model	Genotypes correlated with cancer	Polymorphism associated with tumorigenesis risk	Polymorphism associated with metastasis risk	References
Breast cancer	MMP-9-1562 C/T	Recessive	TT	✓	✓	[34] [35]
Bladder cancer	MMP-9-1562 C/T	Recessive	TT	Unknown	✓	[36]
Colorectal cancer	MMP-9-1562 C/T	Recessive	TT	✓	✓	[37] [38]
Gastric cancer	MMP-9-1562 C/T	Dominant	TT + CT	✓	✓	[39]
Lung cancer	MMP-9-1562 C/T	Dominant	CC + CT	✓	✓	[40]
Lymphoblastic leukemia	MMP-9-1562 C/T	Recessive	TT	✓	✓	[41]
Melanoma	MMP-9 2003 G/A	Recessive	GG	✓	✓	[42]
Oral cancer	MMP-9-1562 C/T	Dominant	CC + CT	✓	Unknown	[43] [44]
Ovarian cancer	rs6094237 (T/A)	Dominant	AT + AA	✓	Unknown	[45]
Prostate cancer	MMP-9-836 A/G	Recessive	AA	✓	Unknown	[46]
Renal cancer	R279Q A/G	Dominant	GG + AG	Unknown	✓	[47]
Thyroid cancer	MMP-9-1562 C/T	Dominant	CT + TT	✓	✓	[48] [49]

The well-known MMP-9-1562 C/T promoter single-nucleotide variation (SNV) is found to be associated with a higher risk of developing many types of cancer with the T-allele being the risk factor, except in the case of lung carcinoma where the wildtype C-allele is found to be correlated with a higher risk of cancer.[40] The MMP-9-2003 G/A and MMP-9-836 A/G SNVs have been shown to be correlated with a higher risk of melanoma and prostate cancer development respectively.[42] [46] Another new polymorphism related to tumorigenesis, which has only been discovered in the case of ovarian cancer is the rs6094237 SNV that has also been shown to affect the vitamin-C receptors.[45] [50]

On the contrary, due to the prometastatic effects of MMP-9, polymorphisms in the respective gene may also lead to poor prognosis in many types of cancer.[51] Interestingly, the MMP-9-1562 C/T and MMP-9 2003 G/A polymorphisms are also associated with a higher risk of cancer migration in various types of cancer.[36] [42] Another polymorphism known as R279Q A/G, which is located in exon 6 of the MMP-9 gene, is associated with a higher risk of aggressive renal cancer and has been shown to be correlated with the histologic grading of renal cancer.[47] It is also worth mentioning that the T-allele of the MMP-9-1562 C/T polymorphism has been found through studies of other diseases to be associated with higher levels of MMP-9 enzyme expression.[52] Therefore, this polymorphism would rationally assist a quicker degradation of the ECM, leading to a higher risk of metastasis. Overall, the evidence from different studies suggests that the polymorphisms of the MMP-9 gene can be used as a potential diagnostic and prognostic genetic marker.

 

MissingLinkText

Regulation of the Matrix Metalloproteinase-9 Gene Expression in Cancer

Different studies have discovered that the levels MMP-9 enzyme is increased in tissue samples and body fluids of cancer patients.[18] This indicates that the expression of the MMP-9 gene is upregulated in cancer patients, which rationally is due to its significant role in the tumor microenvironment. Generally, the expression of MMP-9 is regulated through a variety of genetic mechanisms such as transactivation, as well as epigenetic mechanisms including DNA methylation.[53]

To begin with, different cytokines and chemokines that are expressed in inflammation and cancer can initiate the synthesis of MMP-9 in different tissues. Indeed, cytokines including IL-1β, IL-17α, and tumor necrosis factor-α have been shown to induce the upregulation of the MMP-9 gene by triggering signal transduction pathways that lead to the activation of transcription factors in different types of cancerous cells.[54] [55] [56] It has been demonstrated that the MEK/ERK signaling pathway is the main pathway responsible for inducing MMP-9 expression by activating the p38 protein which in turn acts as a transactivator in DNA transcription.[53] [55] [57] Furthermore, the mutations in the Ras gene that is involved in the oncogenesis process of multiple types of cancer have been shown to increase the activity of the MEK/ERK signaling pathway.[58] [59] In this way, the mutation can promote carcinogenesis and metastases indirectly through the MMP-9 gene.

Simultaneously, studies have shown that the MMP-9 gene is hypomethylated in the case of breast cancer, Ewing's sarcoma and lymphoma cells, and at the same time the gene is upregulated.[60] [61] [62] Indeed, the methylation of DNA inhibits the binding of transcription factors, and therefore, hypomethylation of the gene induces upregulation of its expression.[63] Also, as mentioned previously, the polymorphisms of the MMP-9 gene have also been found to be correlated with higher expression levels of the gene, but the underlying cause of this correlation is still not known.[52]

Overall, all the available evidence indicates that since MMP-9 has a significant role in tumorigenesis and metastasis, one of the possible ways of controlling cancer and metastasis would be to either to inhibit the enzyme directly or inhibit the pathways that lead to the upregulation of the gene. In fact, numerous recent research has been conducted to use MMP-9 as an essential target in medical oncology.[53] Nonetheless, targeting MMP-9 directly has been found to have adverse side effects.[64] Thus, targeting the regulation mechanisms such as the MEK/ERK signaling pathway as an alternative approach can be a promising method that is being considered by many researchers.[65] [66] [67]

 

MissingLinkText

Conclusions and Future Perspectives

As seen in this review, the MMP-9 gene plays a very significant role in cancer generally and various research has been undertaken in recent years to study the gene in more depth. On the one hand, the expression levels of MMP-9 as well as different polymorphisms of the gene have been found to be associated with higher risks of tumorigenesis and poor prognosis in cancer patients. Therefore, the MMP-9 gene can be used as a potential genetic marker that may be able to assist pathologists and medical oncologists in earlier diagnosis of cancer, which will result in better treatment response, as well as predicting the risk of cancer migration. It is worth mentioning that genetic markers of cancer are of paramount significance in the field of oncology in today's era of precision medicine.[68] Nevertheless, for supporting the use of MMP-9 and its polymorphisms as a genetic marker, more clinical trials need to be undertaken.

On the other hand, due to the broad spectrum of the enzyme's action in the development and the progression of neoplastic diseases, the MMP-9 gene as well as its expression mechanisms can be used as potential targets for cancer-targeted therapy. The monoclonal antibody andecaliximab is being studied through different clinical trials as a potential inhibitor of MMP-9; nonetheless, further clinical trials need to be performed before validating its efficacy. Nonetheless, other targets including those which interfere with the expression of MMP-9 can also be used in anticancer therapy.[69] Overall, clinical trials which study the effects of MMP-9 direct or indirect inhibition on the prognosis of patients are required to validate MMP-9 as a target for cancer therapy. A deeper study into the regulation of the MMP-9 gene may also assist the discovery of novel agents which can control tumor progression by inhibiting the expression of MMP-9.

 

MissingLinkText

 

MissingLinkText

Conflict of Interest

None declared.

• 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 label-free 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 metalloproteinases MMP-2 and MMP-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 J Mol 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 gene-environment 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 meta-analysis. 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 matrix metalloproteinase-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 smooth muscle cells in an MMP-9 dependent manner via p38 MAPK 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 kinases with 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 Smad4 mediate 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 of MMP-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 promoter-induced 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

Publication History

Article published online:
17 April 2023