miR-224-5p acts as a tumour suppressor and reverses the resistance to BRAF inhibitor in melanoma through directly targeting PAK4 to block the MAPK pathway

Abstract

miR-224-5p has been shown to play both an oncogene and tumour suppressor role in many human tumours. However, the role and molecular mechanism of miR-224-5p in cutaneous melanoma remains unclear. miR-224-5p levels were downregulated in melanoma tissue, and low miR-224-5p expression was an independent risk factor for melanoma patients. miR-224-5p blocked proliferation, epithelial-to-mesenchymal transition (EMT), invasion, migration in BRAF wild-type melanoma cell, and overcome acquired BRAFi resistance in VMF-resistant melanoma cells. miR-224-5p exerted its role by directly repressing PAK4 to block the downstream CRAF/MEK/ERK pathways. We demonstrated that miR-224-5p inhibited melanoma growth and metastasis in vivo though xenograft tumor and pulmonary metastasis assay. Thus, miR-224-5p/PAK4-mediated CRAF/MEK/ERK pathways have therapeutic potential in melanoma treatment.

Keywords: BRAFi resistance; Growth and metastasis; Melanoma; MiR-224–5p; PAK4.