Abstract
It is reported that microRNAs (miRNA) have paramount functions in many cellular biological processes, development, metabolism, differentiation, survival, proliferation, and apoptosis included, some of which are involved in metastasis of tumors, such as melanoma. Here, three metastasis-associated miRNAs, miR-18a-5p (upregulated), miR-155-5p (downregulated), and miR-93-5p (upregulated), were identified from a total of 63 different expression miRNAs (DEMs) in metastatic melanoma compared with primary melanoma. We predicted 262 target genes of miR-18a-5p, 904 miR-155-5p target genes, and 1220 miR-93-5p target genes. They participated in pathways concerning melanoma, such as TNF signaling pathway, pathways in cancer, FoxO signaling pathway, cell cycle, Hippo signaling pathway, and TGF-beta signaling pathway. We identified the top 10 hub nodes whose degrees were higher for each survival-associated miRNA as hub genes through constructing the PPI network. Using the selected miRNA and the hub genes, we constructed the miRNA-hub gene network, and PTEN and CCND1 were found to be regulated by all three miRNAs. Of note, miR-155-5p was obviously downregulated in metastatic melanoma tissues, and miR-18a-5p and miR-93-5p were obviously regulated positively in metastatic melanoma tissues. In validating experiments, miR-155-5p's overexpression inhibited miR-18a-5p's and miR-93-5p's expression, which could all significantly reduce SK-MEL-28 cells' invasive ability. Finally, miR-93-5p and its potential target gene UBC were selected for further validation. We found that miR-93-5p's inhibition could reduce SK-MEL-28 cell's invasive ability through upregulated the expression of UBC, and the anti-invasive effect was reserved by downregulation of UBC. The results show that the selected three metastasis-associated miRNAs participate in the process of melanoma metastasis via regulating their target genes, providing a potential molecular mechanism for this disease.
Highlights
As the neoplasm of the cells, melanoma starts in skin cells called melanocytes (McComiskey et al, 2015)
We identified 63 different expression miRNAs (DEMs) that were significantly differentially expressed in metastatic melanoma tissues in comparison with primary melanoma tissues, consisting of 50 upregulated and 13 downregulated miRNAs (Supplementary Table 1)
The Gene ontology (GO) biological processes (BP) analysis results demonstrated that miR-155-5p target genes were obviously abundant in cell-cell adhesion, transcription regulated positively/negatively from RNA polymerase II promoter, an apoptotic process regulated negatively, and so on (Figure 2A)
Summary
As the neoplasm of the cells, melanoma starts in skin cells called melanocytes (McComiskey et al, 2015). Environmental factors, for example, ultraviolet light exposure, are considered as the main cause of melanoma (Kanavy and Gerstenblith, 2011). This tumor is predominant in the skin or adjacent to the skin and spread throughout the body (Bakkal et al, 2015), with a dramatically increased global incidence over the past few decades (Azoury and Lange, 2014). There are still no satisfactory treatments for patients with advanced melanoma because of its complex pathogenesis. Like other types of malignant tumors, the main cause of melanoma-related deaths is metastasis (Shaikh et al, 2016). The pathogenesis and inhibition of metastasis have become a focal point of melanoma
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