miR-567 modulates BRAF-mutant melanoma progression through mediating IGF1R, E2F1 and CCNB2

A portion of melanoma patients whose tumors harbor BRAF mutations typically respond initially to BRAF-targeted therapy, acquired resistance remains a major clinical challenge. In this investigation, we discovered new mechanisms and roles of miR-567 in BRAF-mutant melanoma. Expressions of miR-567 were measured by in situ hybridization (ISH) in melanoma tissues. Cell proliferation, migration, and invasion assays or mouse models investigated miR-567 effects in melanoma tumorigenesis or metastasis. The miR-567-inducible clone was used to examine the functions of miR-567 in BRAF-inhibitor resistance. The genes directly targeted by miR-567 were validated via Luciferase reporter assay and Western blot assay. The transcriptomic alteration caused by miR-567 in melanoma cells were analyzed using next-generation sequencing (NGS). Low miR-567 expression was found in melanoma patients with poor responses to BRAF inhibitors, while high expression of miR-567 was correlated with improved overall survival. The levels of miR-567 were decreased in melanoma cell lines and tissues. Upregulation of miR-567 significantly repressed melanoma progression by reducing cell proliferation, migration and invasion, and it also reduced BRAF inhibitor resistance in melanoma cells and suppressed MAPK/ERK and PI3K/AKT signaling pathways. Moreover, E2F1 and CCNB2, IGF1R—a key mediator of melanoma progression and therapeutic resistance—was identified as a direct target gene of miR-567. Additionally, overexpression of miR-567 eliminated the melanoma tumor progression in vivo , especially in inhibition of metastasis. Our findings suggested that miR-567 may represent a potential biomarker and a new therapeutic target in melanoma.