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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.

SUBMITTER: Chen XJ

PROVIDER: S-EPMC8571095 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThymoma and thymic carcinoma are the most frequent subtypes of thymic epithelial tumors (TETs). A relevant advance in TET management could derive from a deeper molecular characterization of these neoplasms. We previously identified a set of microRNA (miRNAs) differentially expressed in TETs and normal thymic tissues and among the most significantly deregulated we described the down-regulation of miR-145-5p in TET. Here we describe the mRNAs diversely regulated in TETs and analyze the correlation between these and the miRNAs previously identified, focusing in particular on miR-145-5p. Then, we examine the functional role of miR-145-5p in TETs and its epigenetic transcriptional regulation.MethodsmRNAs expression profiling of a cohort of fresh frozen TETs and normal tissues was performed by microarray analysis. MiR-145-5p role in TETs was evaluated in vitro, modulating its expression in a Thymic Carcinoma (TC1889) cell line. Epigenetic transcriptional regulation of miR-145-5p was examined by treating the TC1889 cell line with the HDAC inhibitor Valproic Acid (VPA).ResultsStarting from the identification of a 69-gene signature of miR-145-5p putative target mRNAs, whose expression was inversely correlated to that of miR-145-5p, we followed the expression of some of them in vitro upon overexpression of miR-145-5p; we observed that this resulted in the down-regulation of the target genes, impacting on TETs cancerous phenotype. We also found that VPA treatment of TC1889 cells led to miR-145-5p up-regulation and concomitant down-regulation of miR-145-5p target genes and exhibited antitumor effects, as indicated by the induction of cell cycle arrest and by the reduction of cell viability, colony forming ability and migration capability. The importance of miR-145-5p up-regulation mediated by VPA is evidenced by the fact that hampering miR-145-5p activity by a LNA inhibitor reduced the impact of VPA treatment on cell viability and colony forming ability of TET cells. Finally, we observed that VPA was also able to enhance the response of TET cells to cisplatin and erlotinib.ConclusionsAltogether our results suggest that the epigenetic regulation of miR-145-5p expression, as well as the modulation of its functional targets, could be relevant players in tumor progression and treatment response in TETs.

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

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