Mutant p53 Gain-of-Function Induces Migration and Invasion through Overexpression of miR-182-5p in Cancer Cells.

The master-key TP53 gene is a tumor suppressor that is mutated in more than 50% of human cancers. Some p53 mutants lose their tumor suppressor activity and acquire new oncogenic functions, known as a gain of function (GOF). Recent studies have shown that p53 mutants can exert oncogenic effects through specific miRNAs. We identified the differentially expressed miRNA profiles of the three most frequent p53 mutants (p53R273C, p53R248Q, and p53R175H) after their transfection into the Saos-2 cell line (null p53) as compared with p53WT transfected cells. The associations between these miRNAs and the signaling pathways in which they might participate were identified with miRPath Software V3.0. QRT-PCR was employed to validate the miRNA profiles. We observed that p53 mutants have an overall negative effect on miRNA expression. In the global expression profile of the human miRNome regulated by the p53R273C mutant, 72 miRNAs were underexpressed and 35 overexpressed; in the p53R175H miRNAs profile, our results showed the downregulation of 93 and upregulation of 10 miRNAs; and in the miRNAs expression profile regulated by the p53R248Q mutant, we found 167 decreased and 6 increased miRNAs compared with p53WT. However, we found overexpression of some miRNAs, like miR-182-5p, in association with processes such as cell migration and invasion. In addition, we explored whether the induction of cell migration and invasion by the p53R48Q mutant was dependent on miR-182-5p because we found overexpression of miR-182-5p, which is associated with processes such as cell migration and invasion. Inhibition of mutant p53R248Q and miR-182-5p increased FOXF2-MTSS1 levels and decreased cell migration and invasion. In summary, our results suggest that p53 mutants increase the expression of miR-182-5p, and this miRNA is necessary for the p53R248Q mutant to induce cell migration and invasion in a cancer cell model.

A meta-analysis of transcriptome datasets characterizes malignant transformation from melanocytes and nevi to melanoma.

Melanoma represents one of the most aggressive malignancies and has a high tendency to metastasize. The present study aims to investigate the molecular mechanisms of two pathways to cancer transformation with the purpose of identifying potential biomarkers. Our approach is based on a meta-analysis of gene expression profiling contrasting two scenarios: A model that describes a transformation pathway from melanocyte to melanoma and a second model where transformation occurs through an intermediary nevus. Data consists of three independent, publicly available microarray datasets from the Gene Expression Omnibus (GEO) database comprising samples from melanocytes, nevi and melanoma. The present analysis identified 808 differentially expressed genes (528 upregulated and 360 downregulated) in melanoma compared with nevi, and 2,331 differentially expressed genes (946 upregulated and 1,385 downregulated) in melanoma compared with melanocytes. Further analysis narrowed down this list, since 682 differentially expressed genes were found in both models (417 upregulated and 265 downregulated). Enrichment analysis identified relevant dysregulated pathways. This article also presented a discussion on significant genes including ADAM like decysin 1, neudesin neurotrophic factor, MMP19, apolipoprotein L6, C-X-C motif chemokine ligand (CXCL)8, basic, immunoglobulin-like variable motif containing and CXCL16. These are of particular interest because they encode secreted proteins hence represent potential blood biomarkers for the early detection of malignant transformation in both scenarios. Cytotoxic T-lymphocyte associated protein 4, an important therapeutic target in melanoma treatment, was also upregulated in both comparisons indicating a potential involvement in immune tolerance, not only at advanced stages but also during the early transformation to melanoma. The results of the present study may provide a research direction for studying the mechanisms underlying the development of melanoma, depending on its origin.