Regulation of melanoma malignancy by the RP11-705C15.3/miR-145-5p/NRAS/MAPK signaling axis

Abstract

Melanoma is a common lethal skin cancer. Dissecting molecular mechanisms driving the malignancy of melanoma may uncover potential therapeutic targets. We previously identified miR-145-5p as an important tumor-suppressive microRNA in melanoma. Here, we further investigated the roles of long non-coding RNAs (lncRNAs) in melanoma. We identified RP11-705C15.3, a regulator of miR-145-5p, as an oncogenic lncRNA in melanoma. RP11-705C15.3 competitively bound miR-145-5p, relieved the repressive roles of miR-145-5p on its target NRAS, upregulated NRAS expression, and activated MAPK signaling. In vitro functional assays revealed that ectopic expression of RP11-705C15.3 promoted melanoma cell proliferation, inhibited apoptosis, and promoted migration and invasion. Silencing of RP11-705C15.3 repressed melanoma cell proliferation, induced apoptosis, and repressed migration and invasion. Notably, the roles of RP11-705C15.3 in melanoma cell proliferation, apoptosis, migration and invasion are reversed by miR-145-5p overexpression. In vivo functional assays revealed that RP11-705C15.3 promoted melanoma tumor growth and metastasis, which were also reversed by miR-145-5p overexpression. Furthermore, we investigated the expression of RP11-705C15.3 in clinical melanoma tissues and found that RP11-705C15.3 was increased in melanoma tissues. High expression of RP11-705C15.3 was positively correlated with thickness, ulceration, metastasis, and inferior overall survival. Taken together, our findings suggest RP11-705C15.3 as a novel oncogene in melanoma, and highlight that the RP11-705C15.3/miR-145-5p/NRAS/MAPK signaling axis may be potential therapeutic targets for melanoma.