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MiR-146a promotes the initiation and progression of melanoma by activating Notch signaling

ABSTRACT: Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. Here we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE39983 | GEO | 2014/02/18

SECONDARY ACCESSION(S): PRJNA172202

REPOSITORIES: GEO

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miR-146a promotes the initiation and progression of melanoma by activating Notch signaling

Project description:Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. Here we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma.

2014-02-18 | GSE39294 | GEO

miR-146a promotes the initiation and progression of melanoma by activating Notch signaling

2014-02-18 | E-GEOD-39294 | biostudies-arrayexpress

miR-146a promotes the initiation and progression of melanoma by activating Notch signaling

2014-02-18 | E-GEOD-39983 | biostudies-arrayexpress

Transcriptional profiles of NRAS- and BRAF-mutant melanoma cell lines under normal conditions and in response to glucose starvation

Project description:NRAS and BRAF are the most commonly found genetic alterations in melanoma. It has been demonstrated that NRAS and BRAF oncogenic alterations, even affecting the same signaling pathway, represent two different clinical and biochemical entities, showing different signaling patterns and biological responses. Metabolic reprogramming is considered a novel target to control cancer; however, it is mostly unknown how the NRAS oncogene contributes to this cancer hallmark. We have showed that NRAS-mutated melanomas harbor specific metabolic alterations that render cells sensitive to RAS pathway inhibition upon metabolic stress. Gene expression analysis has confirmed different transcriptional profiles of NRAS- and BRAF- mutant cells both, under basal conditions and in response to glucose starvation. Moreover, analysis of glucose metabolism-related genes expression regulation revealed PFKFB2 as an important player linking glycolysis and RAS pathway activation.

2022-08-31 | E-MTAB-10921 | biostudies-arrayexpress

miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization.

Project description:Malignant melanoma is the most aggressive form of skin cancer therefore it is crucial to disclose its underlying molecular mechanisms. MicroRNAs are small endogenous non-coding RNAs able to post-transcriptionally down-regulate the expression of direct target genes. Using a melanoma progression model, we identified miR-146a as a key double-acting player in melanoma malignancy. In fact, miR-146a is able to enhance tumor growth while it suppresses dissemination. We evidenced that melanoma cell growth is coordinated by its direct target lunatic fringe (LFNG) which operates on the NOTCH/PTEN/Akt pathway. Instead, metastasis formation inhibition is linked to decreased expression of ITGAV and ROCK1. Relevantly, miR-146a expression correlates with melanoma recurrence and it is enriched both in patients-derived melanoma and cutaneous metastasis samples, while its direct targets are depleted. However, miR-146a levels drop in Circulating Tumor Cells, suggesting the necessity for miR-146a expression to fluctuate during tumor progression in order to favor tumor growth and allow dissemination. This study reconciles the contradictory biological functions of miR-146a in melanoma progression and unravels distinct molecular mechanisms that need to be considered for therapeutic interventions.

2016-03-18 | GSE77090 | GEO

Transcriptional response to TNF-alpha in a panel of 17 human melanoma cell lines

2014-02-10 | GSE51221 | GEO

Transcriptional response to TNF-alpha in a panel of 17 human melanoma cell lines

Project description:A panel of 17 human melanoma cell lines with known BRAF and NRAS mutation status was stimulated with TNF-alpha for 72 hours. The goal of the study was to correlate the transcriptional response in BRAF versus NRAS mutated melanoma cell lines. Total RNA was obtained from a panel of 17 human melanoma cell lines treated for 72 hours with TNF-alpha or left untreated. Gene expression profiling was done using the Illumina Human HT12 v4 platform.

2014-02-10 | E-GEOD-51221 | biostudies-arrayexpress

Role of PLK1 in epithelial-mesenchymal transition in human melanoma

Project description:Polo-like kinase 1 (PLK1), a serine/threonine kinase and important cell cycle regulator, is overexpressed in melanoma and its expression has been associated with poor disease prognosis. PLK1 has been shown to interact with NUMB, a NOTCH antagonist. However, the exact role of PLK1-NUMB-NOTCH axis in epithelial-mesenchymal transition (EMT) and melanoma progression is unclear. In this study, Affymetrix microarray analysis was performed to determine differentially expressed genes following doxycyclin induced shRNA-mediated knockdown of PLK1 in human melanoma cells that showed significant modulations in EMT and metastasis related genes.

2024-01-01 | GSE237385 | GEO

CDK11 loss induces cell cycle dysfunction and death of BRAF and NRAS melanoma cells

Project description:Cyclin dependent kinase 11 (CDK11) is a protein kinase that regulates RNA transcription, pre-mRNA splicing, mitosis, and cell death. Targeting of CDK11 expression levels is effective in the experimental treatment of breast and other cancers, but these data are lacking in melanoma. To understand CDK11 function in melanoma, we evaluated protein and RNA levels of CDK11, Cyclin L1 and Cyclin L2 in benign melanocytes and BRAF- as well as NRAS-mutant melanoma cell lines. We investigated the effectiveness of reducing expression of this survival kinase using RNA interference on viability, clonal survival, and tumorsphere formation in melanoma cell lines. We examined the impact of CDK11 loss in BRAF-mutant melanoma on more than 700 genes important in cancer signaling pathways. Follow-up analysis evaluated how CDK11 loss alters cell cycle function in BRAF- and NRAS-mutant melanoma cells. We present data on CDK11, CCNL1 and CCNL2 mRNA expression in melanoma patients, including prognosis for survival. In sum, we found that CDK11 is necessary for melanoma cell survival, and a major impact of CDK11 loss in melanoma is to cause disruption of the cell cycle distribution with accumulation of G1- and loss of G2/M-phase cancer cells.

2019-05-08 | GSE128693 | GEO

Mapping heterogeneity in a patient-derived melanoma culture by single-cell RNA-seq

Project description:Recent technological advances in single-cell genomics make it possible to analyze cellular heterogeneity of tumor samples. Here, we applied single-cell RNA-seq to measure the transcriptomes of 307 single cells cultured from three biopsies of three different patients with a BRAF/NRAS wild type, BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant melanoma metastasis, respectively. Analysis based on self-organizing maps identified sub-populations defined by multiple gene expression modules involved in proliferation, oxidative phosphorylation, pigmentation and cellular stroma. Gene expression modules had prognostic relevance when compared with gene expression data from published melanoma samples and patient survival data. We surveyed kinome expression patterns across sub-populations of the BRAF/NRAS wild type sample and found that CDK4 and CDK2 were consistently highly expressed in the majority of cells, suggesting that these kinases might be involved in melanoma progression. Treatment of cells with the CDK4 inhibitor palbociclib restricted cell proliferation to a similar, and in some cases greater, extent than MAPK inhibitors. Finally, we identified a low abundant sub-population in this sample that highly expressed a module containing ABC transporter ABCB5, surface markers CD271 and CD133, and multiple aldehyde dehydrogenases (ALDHs), as markers for melanoma stem or initiating cells. Patient-derived cultures of the BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant metastases showed more homogeneous single-cell gene expression patterns with gene expression modules for proliferation and ABC transporters. Taken together, our results describe an intertumor and intratumor heterogeneity in melanoma short-term cultures which might be relevant for patient survival, and suggest promising targets for new treatment approaches in melanoma therapy.

2017-01-12 | GSE81383 | GEO

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