Functional Roles of Matrix Metalloproteinases and Their Inhibitors in Melanoma

Abstract

The extracellular matrix (ECM) plays an important role in the regulation of the tissue microenvironment and in the maintenance of cellular homeostasis. Several proteins with a proteolytic activity toward several ECM components are involved in the regulation and remodeling of the ECM. Among these, Matrix Metalloproteinases (MMPs) are a class of peptidase able to remodel the ECM by favoring the tumor invasive processes. Of these peptidases, MMP-9 is the most involved in the development of cancer, including that of melanoma. Dysregulations of the MAPKs and PI3K/Akt signaling pathways can lead to an aberrant overexpression of MMP-9. Even ncRNAs are implicated in the aberrant production of MMP-9 protein, as well as other proteins responsible for the activation or inhibition of MMP-9, such as Osteopontin and Tissue Inhibitors of Metalloproteinases. Currently, there are different therapeutic approaches for melanoma, including targeted therapies and immunotherapies. However, no biomarkers are available for the prediction of the therapeutic response. In this context, several studies have tried to understand the diagnostic, prognostic and therapeutic potential of MMP-9 in melanoma patients by performing clinical trials with synthetic MMPs inhibitors. Therefore, MMP-9 may be considered a promising molecule for the management of melanoma patients due to its role as a biomarker and therapeutic target.

The double effect of walnut septum extract (Juglans regia L.) counteracts A172 glioblastoma cell survival and bacterial growth

“…The ability of the walnut septum extract to decrease A172 cell proliferation and migration led to the hypothesis that it could exert a pro-apoptotic action or act against proteases and proteins that favor cell invasion and migration. This has been supported from preliminary animal studies, which found that walnut extracts were effective in reducing the concentration of matrix metalloproteinases at the mRNA and protein level, that are well-known to be involved in tumor invasion ( 78 - 80 ). In the same manner, several studies have demonstrated the pro-apoptotic action of walnut septum polyphenols for example, in human breast cancer cell lines implanted in nude mice, and in mammary gland, prostate, colon, and renal cancers tumors in transgenic mouse models ( 62 , 81 ).…”

Cutaneous melanoma and the immunotherapy revolution (Review)

“…Recently, a growing body of evidence is trying to correlate ICI efficacy to the expression levels of PD-L1 detected in circulating tumor DNA (105,106). Finally, studies have proposed the analysis of matrix metalloproteinase (MMPs), known to be strictly involved in melanoma growth (107,108), as good indicator of response to immunotherapy. Moogk and colleagues (109) showed an inverse association between anti-tumor T-cell response and MMP-23 expression in primary melanoma tumors treated with adjuvant immunotherapy.…”

Current and Future Trends in Molecular Biomarkers for Diagnostic, Prognostic, and Predictive Purposes in Non-Melanoma Skin Cancer

“…Intense research in cancer biology has identified global genomic hypomethylation as one of the leading factors for genomic instability and oncogene activation, whereas a number of tumor suppressor genes are silenced due to hypermethylated CpG islands [ 96 ], while global hypomethylation of lamina-associated domains (LAD) may be another aspect of the deregulated methylome [ 97 ]. In cutaneous melanoma, it was demonstrated that promoter hypomethylation and intragenic hypermethylation of specific genes are associated with tumor aggressiveness due to the alteration of extracellular matrix components and the upregulation of matrix metalloproteinases [ 98 , 99 , 100 ]. This highlights the clinical potential of deregulated methylation status as a hallmark for carcinogenesis, allowing the recognition of various methylation patterns as biomarkers for diagnosis and prognosis [ 101 ] ( Table 1 ).…”