Circ17399 RNA promotes melanoma progression through the miR-150-3p/ITM2C Axis and ALKBH5-mediated FOXM1 m6A modification

Abstract

Skin cutaneous melanoma (SKCM) is a highly aggressive malignancy with a poor prognosis, necessitating the exploration of novel molecular mechanisms driving its progression. CircRNA, which have emerged as critical regulators in cancer biology, have been implicated in various tumorigenic processes. However, their specific roles in SKCM remain inadequately understood. Bioinformatics analyses of TCGA and GEO datasets identified circ17399 as a candidate oncogenic circRNA. Functional validation was performed using in vitro (A375, A2058 cells) and in vivo models. Techniques included qRT-PCR, dual-luciferase reporter assays, RNA FISH, Western blot, Transwell assays, and MeRIP-qPCR. Circ17399 knockdown/overexpression, miR-150-3p modulation, and ALKBH5/FOXM1 interaction studies were conducted to dissect its regulatory network. Circ17399 was significantly upregulated in SKCM tissues and correlated with poor prognosis. Mechanistically, circ17399 sponged miR-150-3p to derepress ITM2C, enhancing SKCM cell proliferation, migration, and invasion. Concurrently, circ17399 bound ALKBH5, reducing m6A methylation on FOXM1 mRNA, thereby stabilizing FOXM1 and promoting tumor progression. In vivo, circ17399 knockdown suppressed tumor growth and metastasis, while overexpression exacerbated malignancy. Circ17399 promotes melanoma progression by competitively binding miR-150-3p to upregulate ITM2C and recruiting ALKBH5 to reduce m6A methylation of FOXM1, enhancing its stability and oncogenic function. These findings unveil a dual-axis regulatory mechanism in SKCM pathogenesis and position circ17399 as a promising diagnostic biomarker and actionable therapeutic target for melanoma intervention.