Elias Katsoulieris, Paraskevi Ioannou, Nikolaos A. Afratis
Modulation of extracellular matrix (ECM) turnover is a critical prerequisite process underlying the onset of melanoma metastasis. ECM proteases are involved in the degradation of matrix components during ECM turnover, which is associated with melanoma cell growth, migration, invasion, extravasation, metastasis, and modulation of melanoma tumor immunogenicity. During these processes, fluctuations in ECM protease activities and concentrations occur in response to complex regulatory mechanisms acting at both the transcriptional and post-transcriptional levels of protease gene expression. In this review, we examine the major factors of epigenetic machinery, specifically protease-regulating microRNAs (miRNAs), with respect to their ability to directly target ECM protease transcripts and influence melanoma progression. Furthermore, given that dysregulation of the intestinal microbiota has been identified as an etiological factor in melanoma resistance to contemporary immunotherapies, this review examines evidence linking gut dysbiosis-induced changes in matrix metalloproteinase-targeting miRNA profiles to the progression of melanoma. In conclusion, we evaluate the therapeutic potential of approaches involving modifications of gut microbiota populations, alongside direct miRNA targeting of ECM proteases. The integration of these strategies may facilitate the development of innovative adjuvant therapies aimed at overcoming resistance to current inhibitor checkpoint immunotherapies.