Expression of microRNAs and their target genes in melanomas originating from gynecologic sites
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ABSTRACT:
PROVIDER: PRJNA858668 | ENA |
REPOSITORIES: ENA
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Project description:Melanomas from gynecologic sites (MOGS) are rare and have poor survival. MicroRNAs (miRs) regulate gene expression and are dysregulated in cancer. We hypothesized that MOGS would display unique miR and mRNA expression profiles. The miR and mRNA expression profile in RNA from formalin fixed, paraffin embedded vaginal melanomas (relative to vaginal mucosa) and vulvar melanomas (relative to cutaneous melanoma) were measured with the Nanostring Human miRNA assay and Tumor Signaling mRNA assay. Differential patterns of expression were identified for 21 miRs in vaginal and 47 miRs in vulvar melanoma (fold change >2, p<0.01). In vaginal melanoma, miR-145-5p (tumor suppressor targeting TLR4, NRAS) was downregulated and miR-106a-5p, miR-17-5p, miR-20b-5p (members of miR-17-92 cluster) were upregulated. In vulvar melanoma, known tumor suppressors miR-200b-3p and miR-200a-3p were downregulated, and miR-20a-5p and miR-19b-3p, from the miR-17-92 cluster, were upregulated. Pathway analysis showed an enrichment of "proteoglycans in cancer". Among differentially expressed mRNAs, topoisomerase IIα (TOP2A) was upregulated in both MOGS. Gene targets of dysregulated miRs were identified using publicly available databases and Pearson correlations. In vaginal melanoma, suppressor of cytokine signaling 3 (SOCS3) was downregulated, was a validated target of miR-19b-3p and miR-20a-5p and trended toward a significant inverse Pearson correlation with miR-19b-3p (p = 0.093). In vulvar melanoma, cyclin dependent kinase inhibitor 1A (CDKN1A) was downregulated, was the validated target of 22 upregulated miRs, and had a significant inverse Pearson correlation with miR-503-5p, miR-130a-3p, and miR-20a-5p (0.005 < p < 0.026). These findings support microRNAs as mediators of gene expression in MOGS.
| S-EPMC10309992 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-07-16 | GSE208180 | GEO
Project description:Cutaneous, ocular and mucosal melanomas are histologically indistinguishable tumors that are driven by different spectrum of genetic alterations. With current methods, identification of the site of origin of a melanoma metastasis is challenging, in particular when the metastasis is the first tumor manifestation. Genome wide DNA methylation profiling has shown promise for the identification of the site of tumor origin in various settings. Here we explore the DNA methylation landscape of melanomas from different sites and analyze if different melanoma origins can be distinguished by their epigenetic profile. We performed DNA methylation analysis, next generation DNA panel sequencing and copy number analysis of 82 non-cutaneous and 25 cutaneous melanoma samples. We further analyzed eight normal melanocyte cell culture preparations by DNA methylation profiling. DNA methylation analysis clearly separated uveal melanomas from melanomas of other primary sites while mucosal, conjunctival and cutaneous melanomas were epigenetically almost identical. Still, we observed DNA methylation differences in cancer-related genes, such as low frequencies of RARB and CDKN2A promoter methylation in mucosal melanomas, while conjunctival melanomas frequently harbored APC promoter methylation. Furthermore, all investigated melanomas of the paranasal sinus showed loss of PTEN expression, mainly caused by promoter methylation. This was less frequently seen in melanomas of other sites. Copy number analysis revealed recurrent amplifications in mucosal melanomas, including chromosome 4q, 5p, 11q and 12q. Most melanomas of the oral cavity showed gains of chromosome 5p with TERT amplification while 11q amplifications were enriched in melanomas of the nasal cavity. Mucosal, conjunctival and cutaneous melanomas show a surprisingly similar DNA methylation profile and identification of the site of origin by DNA methylation testing is likely not feasible. Still, our study shows that there are DNA methylation differences on the gene level in known tumor drivers, related to the anatomical primary site.
2021-09-21 | GSE178416 | GEO
Project description:MicroRNAs (miRNAs) function as endogenous translational repressors of protein-coding genes in animals by binding to target sites in the 3' UTRs of mRNAs. Because a single nucleotide change in the sequence of a target site can affect miRNA regulation, naturally occurring SNPs in target sites are candidates for functional variation that may be of interest for biomedical applications and evolutionary studies. However, little is known to date about variation among humans at miRNAs and their target sites. In this study, we analyzed publicly available SNP data in context with miRNAs and their target sites throughout the human genome, and we found a relatively low level of variation in functional regions of miRNAs, but an appreciable level of variation at target sites. Approximately 400 SNPs were found at experimentally verified target sites or predicted target sites that are otherwise evolutionarily conserved across mammals. Moreover, approximately 250 SNPs potentially create novel target sites for miRNAs in humans. If some variants have functional effects, they might confer phenotypic differences among humans. Although the majority of these SNPs appear to be evolving under neutrality, interestingly, some of these SNPs are found at relatively high population frequencies even in experimentally verified targets, and a few variants are associated with atypically long-range haplotypes that may have been subject to recent positive selection.
| S-EPMC1805605 | biostudies-literature
Project description:The importance of microRNAs (miRs) in control of gene expression is now clearly recognized. While individual microRNAs are thought to target hundreds of disparate mRNAs via imperfect base pairing, little is known about the characteristics of miR target sites. Here we show that the miRs can be aligned with empirically identified accessible sites in a target RNA (Cytokeratin 19, KRT), and that some of the aligned miRs functionally down-regulate KRT expression post-transcriptionally. We employed an RNase-H-based random library selection protocol to identify accessible sites in KRT RNA. We then aligned the Sanger Institute database collection of human miRs to KRT mRNA, and also aligned them using the web-based MicroInspector program. Most miRs aligned with the accessible sites identified empirically; those not aligned with the empirically identified sites also functioned effectively in RNase-H-based assays. Similar results were obtained with a second target RNA (Mammoglobin). Transient transfection assays established that some of the miRs which aligned with KRT significantly down-regulated it at the protein level, with no effect on RNA level. The functionally effective miRs aligned within the coding region of KRT, whereas a number of miRs which aligned with the 3'-untranslated region did not produce down-regulation.
| S-EPMC4578708 | biostudies-other
Project description:Primary uveal melanomas show multiple genetic alterations. To determine mutational status of six human primary uveal melanomas, we performed whole exome sequencing (WES) and called Single Nucleotide Polimorphism (SNPs) to identify somatic mutations in these human primary uveal melanomas.
2021-01-25 | GSE138664 | GEO
Project description:Molecular characterization of mucosal melanomas
| PRJNA470997 | ENA
Project description:Molecular characterization of mucosal melanomas
| PRJNA470998 | ENA
Project description:Primary uveal melanomas show multiple chromosomal aberrations. To identify genome variation in six human primary uveal melanomas, genome wide copy number variation (CNV) analyses were carried out in human primary uveal melanoma samples using array comparative genome hybridization.
2021-01-25 | GSE138404 | GEO
Project description:microRNA dysregulation is a common feature of cancer cells, but the complex roles of microRNAs in cancer are not fully elucidated. Here we used functional genomics to identify oncogenic microRNAs in non-small cell lung cancer and to evaluate their impact on response to EGFR targeting therapy. Our data demonstrate that microRNAs with an AAGUGC-motif in their seed-sequence increase both cancer cell proliferation and sensitivity to EGFR inhibitors. Global transcriptomics, proteomics and target prediction resulted in the identification of several tumor suppressors involved in the G1/S transition as targets of AAGUGC-microRNAs. The clinical implications of our findings were evaluated by analysis of public domain data supporting the link between this microRNA seed-family, their tumor suppressor targets and cancer cell proliferation. In conclusion we propose that AAGUGC-microRNAs are an integral part of an oncogenic signaling network, and that these findings have potential therapeutic implications, especially in selecting patients for EGFR-targeting therapy.
2017-03-31 | MSV000080829 | MassIVE