| dc.description.abstract | Even more advancements in the treatment of melanoma such as target therapy and immunotherapy are now available; unfortunately, a subset of patients do not benefit or produced resistance to these approaches. Therefore, an urgent need to develop an alternative strategy should be investigated to further improve clinical benefits. It is well established that MAPK/ERK pathway plays a major role in the progression of melanoma. Interestingly, our previous microarray result observed that there are 22 miRNAs related to the status of MAPK/ERK pathway. In this context, we were interested in the functions of two candidate miRNAs, miR-524-5p and miR-567, in the development of melanoma and BRAF inhibitor-resistant melanoma.
Our previous study showed that overexpression of miR-524-5p reduced the development of melanoma cells. However, the biological functions of miR-524-5p and its mechanism underlying BRAF inhibitor resistance are still unknown. Therefore, in this study, we focused on the functions of miR-524-5p in BRAF inhibitor-resistant melanoma cells. The results showed that expression of miR-524-5p was higher in complete response and long-term partial response as compared to short-term partial response and progressive disease in patients treated with BRAF inhibitors. This finding suggested that miR-524-5p was involved in the response of melanoma patients to BRAF inhibitors. Of note, overexpression of miR-524-5p reduced the development of melanoma in vivo and in vitro. Reactivation of MAPK/ERK pathway was observed in resistant cells and overexpression of miR-524-5p downregulated the activity of this pathway by decreasing the phosphorylation of MEK1/2 and ERK1/2.
Expression of miR-567, another potential miRNA candidate, was decreased in melanoma cells and melanoma tissues as compared to melanocyte cells and nevus tissues. Of note, staining expression of miR-567 was more accurately differentiate between melanoma and nevus tissues as compared to staining of miR-524-5p. Overexpression of miR-567 in melanoma cells significantly reduced proliferation, survival, anchorage-independent growth, migratory, and invasive abilities. In addition, knockdown of miR-567 direct targets, IGF1R, E2F1, and Cyclin B2, attenuated proliferation and survival of melanoma cells. Interestingly, introduction of miR-567 downregulated MAPK/ERK and PI3K/AKT pathways in melanoma cells. Moreover, overexpression of miR-567 reduced the promoting tumor growth of melanoma cells induced by macrophages, indicating the involvement of miR-567 in tumor microenvironment.
In conclusion, these results increased the knowledge about the biological roles and mechanisms underlying miR-524-5p and miR-567 mediated tumorigenesis and BRAF inhibitor resistance. The findings suggested that miR-524-5p and miR-567 could be served not only as biomarkers but also as potential molecular targets for prevention of melanoma progression. | en_US |