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Tissue microRNA expression profiling in hepatic and pulmonary metastatic melanoma.

ABSTRACT: Malignant melanoma has a propensity for the development of hepatic and pulmonary metastases. MicroRNAs (miRs) are small, noncoding RNA molecules containing about 22 nucleotides that mediate protein expression and can contribute to cancer progression. We aim to identify clinically useful differences in miR expression in metastatic melanoma tissue. RNA was extracted from formalin-fixed, paraffin-embedded samples of hepatic and pulmonary metastatic melanoma, benign, nevi, and primary cutaneous melanoma. Assessment of miR expression was performed on purified RNA using the NanoString nCounter miRNA assay. miRs with greater than twofold change in expression when compared to other tumor sites (P value ≤ 0.05, modified t-test) were identified as dysregulated. Common gene targets were then identified among dysregulated miRs unique to each metastatic site. Melanoma metastatic to the liver had differential expression of 26 miRs compared to benign nevi and 16 miRs compared to primary melanoma (P < 0.048). Melanoma metastatic to the lung had differential expression of 19 miRs compared to benign nevi and 10 miRs compared to primary melanoma (P < 0.024). Compared to lung metastases, liver metastases had greater than twofold upregulation of four miRs, and 4.2-fold downregulation of miR-200c-3p (P < 0.0081). These findings indicate that sites of metastatic melanoma have unique miR profiles that may contribute to their development and localization. Further investigation of the utility of these miRs as diagnostic and prognostic biomarkers and their impact on the development of metastatic melanoma is warranted.

SUBMITTER: DiVincenzo MJ

PROVIDER: S-EPMC7484309 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe role of microRNAs (miRNAs) in the pathogenesis of systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) remains to be fully elucidated. This study evaluated the expression profile of miRNAs in the lung tissue of patients with SSc-PAH.MethodsLung tissue samples were collected from 3 SSc-PAH patients and 4 healthy controls. A small RNA high throughput sequence approach was used for screening the differentially expressed miRNAs in the lung tissue samples. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate 4 highly significant differentially expressed miRNAs. Gene Ontology and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis for mRNAs were performed using the R package clusterProfiler software.ResultsA total of 82 upregulated miRNAs and 35 downregulated miRNAs were detected in the lung tissues of patients with SSc-PAH compared with healthy controls. GO enrichment analysis demonstrated that the upregulated target genes were closely involved in biological processes such as nervous system development, anatomical structure morphogenesis, system development, cellular macromolecule metabolic processes, and cellular processes. The downregulated target genes were involved in the plasma membrane bound cell projection morphogenesis and the regulation of macromolecule metabolic processes. The KEGG enrichment analysis showed that the upregulated genes were associated with important pathways involved in cancer biology, and the target genes of the downregulated miRNAs were involved in axon guidance. High throughput sequencing and qRT-PCR revealed that hsa-miR-205-5p and hsa-miR-539-3p were differentially expressed in SSc-PAH tissue. The target genes of hsa-miR-205-5p and hsa-miR-539-3p, IRF1and ADCYAP1, respectively, were verified using the high throughput dataset GSE48149.ConclusionsmiRNAs may play an important role in the pathogenesis of SSc-PAH, and hsa-miR-205-5p and hsa-miR-539-3p may be potential therapeutic targets in patients with SSc-PAH.

Project description:Breast cancer (BC) is the foremost cause of cancer-related deaths in women. BC patients are oftentimes presented with lymph node metastasis (LNM), which increases their risk of recurrence. Compelling data have recently implicated microRNAs in promoting BC metastasis. Therefore, the identification of microRNA (miRNA)-based molecular signature associated with LNM could provide an opportunity for a more personalized treatment for BC patients with high risk of LNM. In current study, we performed comprehensive miRNA profiling in matched primary breast and LNM and identified 40 miRNAs, which were differentially expressed in LNM compared to primary tumors. The expression of 14 miRNAs (Up: hsa-miR-155-5p, hsa-miR-150-5p, hsa-miR-146a-5p, hsa-miR-142-5p and down: hsa-miR-200a-3p, hsa-miR-200b-3p, hsa-miR-200c-3p, hsa-miR-205-5p, hsa-miR-210-3p, hsa-miR-214-3p, hsa-miR-141-3p, hsa-miR-127-3p, hsa-miR-125a-5p, and hsa-let-7c-5p) was subsequently validated in a second cohort of 32 breast and 32 matched LNM tumor tissues. Mechanistically, forced expression of hsa-miR-205-5p, or hsa-miR-214-3p epigenetically inhibited MDA-MB-231 cell proliferation, colony formation, and cell migration. Global gene expression profiling on MDA-MB-231 cells overexpressing hsa-miR-205-5p, or hsa-miR-214-3p in combination with in silico target prediction and ingenuity pathway analyses identified multiple bona fide targets for hsa-miR-205-5p, hsa-miR-214-3p affecting cellular proliferation and migration. Interestingly, interrogation of the expression levels of hsa-miR-205 and hsa-miR-214 in the METABRIC breast cancer dataset revealed significantly poor overall survival in patients with downregulated expression of miR-205 [HR = 0.75 (0.61-0.91)], p = 0.003 and hsa-miR-214 [HR = 0.74 (0.59-0.93) p = 0.008]. Our data unraveled the miRNA-transcriptional landscape associated with LNM and provide novel insight on the role of several miRNAs in promoting BC LNM, and suggest their potential utilization in the clinical management of BC patients.

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Tissue microRNA expression profiling in hepatic and pulmonary metastatic melanoma.

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