Abstract
Melanoma is a skin malignancy with a high mutation frequency of genetic alterations. MicroRNA (miR)-200b-3p is involved in various cancers, while in melanoma its bio-function remains unknown. In this study, we found that miR-200b-3p was down-regulated in melanoma tissues and cell lines compared to benign nevus cells. Overexpression of miR-200b-3p significantly inhibited the proliferation and invasion of melanoma cells. According to bioinformatics analysis and sequencing data, we supposed that SMAD family member 2 (SMAD2) was the target gene and nuclear enriched abundant transcript 1 (NEAT1) was the upstream long non-coding RNA (lncRNA) of miR-200b-3p. These predictions were verified by western blotting and quantitative real-time reverse transcription PCR (RT-qPCR). Luciferase reporter assays revealed that NEAT1 up-regulated SMAD2 by directly sponging miR-200b-3p. In vitro and in vivo, we demonstrated that both NEAT1 and SMAD2 could promote the proliferation and invasion of melanoma cells, and these effects were reversed by up-regulating miR-200b-3p. In addition, NEAT1/miR-200b-3p/SMAD2 axis promoted melanoma progression by activating EMT signaling pathway and immune responses. Taken together, the NEAT1/miR-200b-3p/SMAD2 signaling pathway promotes melanoma via activation of EMT, cell invasion and is related with immune responses, which provides new insights into the molecular mechanisms and therapeutic targets for melanoma.
Highlights
Melanoma is one of the most malignant skin cancers with an increasing incidence [1], and accounts for approximately 80% skin-cancer related deaths in the worldwide [2]
MiRNAs, which are characterized as small, singlestranded noncoding RNAs, can target specific mRNAs to inhibit protein translation. miR200b-3p is an important member of the miR-200 family, which is associated with epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET), cancer cell proliferation, and drug resistance [5, 6]
Considering the correlations among miR-200b-3p, SMAD family member 2 (SMAD2) and nuclear enriched abundant transcript 1 (NEAT1), the aim of this study is to investigate biofunction of NEAT1/miR-200-3p/SMAD2 axis in melanoma and explore its potential as a novel biomarker and therapeutic target of melanoma
Summary
Melanoma is one of the most malignant skin cancers with an increasing incidence [1], and accounts for approximately 80% skin-cancer related deaths in the worldwide [2]. Genetic landscape of malignancies demonstrates that melanoma involves the highest mutation frequency of genetic alterations among all cancers analyzed [3]. It is essential to identify potential genetic biomarkers www.aging-us.com providing new insight into the mechanism of tumorigenesis and progression of melanoma. MiR200b-3p is an important member of the miR-200 family, which is associated with epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET), cancer cell proliferation, and drug resistance [5, 6]. Little is known about the roles of miR200b-3p in melanoma progression, especially its signaling pathway, crosstalk with some lncRNAs and proteins in the tumorigenesis
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