New target genes of MITF-induced microRNA-211 contribute to melanoma cell invasion
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Muller Arnaud
PROVIDER: S-ECPF-MEXP-3749 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:The non-coding microRNAs (miRNA) have tissue- and disease-specific expression patterns. They down-regulate target mRNAs, which likely impacts on most fundamental cellular processes. Differential expression patterns of miRNAs are currently being exploited for identification of biomarkers for early disease diagnosis, prediction of progression for melanoma and other cancers and as promising drug targets, since they can easily be inhibited or replaced in a given cellular context. Before successfully manipulating miRNAs in clinical settings, their precise expression levels, endogenous functions and thus their target genes have to be determined. MiR-211, a melanocyte lineage-specific small non-coding miRNA, is located in an intron of TRPM1, a target gene of the microphtalmia-associated transcription factor (MITF). By transcriptionally up-regulating TRPM1, MITF, which is critical for both melanocyte differentiation and survival and for melanoma progression, indirectly drives the expression of miR-211. Expression of this miRNA is often reduced in melanoma samples. Here, we investigated functional roles of miR-211 by identifying and studying new target genes. We show that MITF-correlated miR-211 expression levels are mostly but not always reduced in a panel of 11 melanoma cell lines and in primary and metastatic melanoma compared to normal melanocytes and nevi, respectively. MiR-211 itself only marginally impacted on cell invasion and migration, while perturbation of some new miR-211 target genes, such as AP1S2, SOX11, IGFBP5, and SERINC3 significantly increased invasion. These results and the variable expression levels of miR-211 raise serious doubts on the value of miR-211 as a melanoma tumor-suppressing miRNA and/or as a biomarker for melanoma.
| S-EPMC3764006 | biostudies-literature
Project description:IGR39 cells, seeded at a density of 6x104 cells/well in 12-well culture plates, were transfected with 5 nM of miR-211 mimic or negative control (NCM) as described in the main text. Samples for total RNA extraction were collected 48h after transfection. RNA quality was assessed using RNA 6000 NanoChips with the Agilent 2100 Bioanalyzer (Agilent, Paolo Alto, USA). Gene expression profiling experiments using GeneChipM-. Human Gene 2.0 ST arrays and miRNA profiling using GeneChipM-. miRNA arrays (Affymetrix, Santa Clara, CA, USA) were performed on two independent samples at the CRP-SantM-i Microarray Unit (Luxembourg) as described before (Reinsbach et al., 2012) and according to standard protocols. Standard pipeline from the PartekM-. Genomics SuiteTM (Partek GS) software was used for analysis of data files. Lists of genes were generated by pair-wise comparison of expression data sets (negative control vs. mimic treated samples at 48h).
2013-08-01 | E-MEXP-3749 | biostudies-arrayexpress
Project description:Melanoma tumors are highly heterogeneous, comprising of different cell types that vary in their potential for growth and invasion. Heterogeneous expression of the Microphthalmia-associated Transcription Factor (MITF) and the POU domain transcription factor BRN2 (POU3F2) has been found in malignant melanoma. Changing expression of these transcription factors as the disease progresses has been linked to the metastatic mechanism of phenotype switching. We therefore investigated the effects of MITF and BRN2 expression in melanoma growth and metastasis. Depletion of MITF resulted in a cell population that had a slowed cell cycle progression, was less invasive in vitro and had hindered tumor and metastasis forming ability in mouse xenograft studies. BRN2 depletion left a cell population with intact proliferation and invasion in vitro; however metastatic growth was significantly reduced in the mouse xenograft model. These results suggest that the proliferative population within melanoma tumors express MITF, and both MITF and BRN2 are important for metastatic growth in vivo. This finding highlights the importance of BRN2 and MITF expression in development of melanoma metastasis.
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Project description:The clinical management of malignant melanoma remains a challenge because these tumors are intrinsically aggressive and prone to therapeutic resistance. MicroRNA (miR)-211 is an emerging melanoma oncogene. Melanoma metabolism adapts to promote survival, including in response to BRAFV600E inhibition, but how miR-211 participates in this process is unknown. Here, we generated miR-211 loss-of-function cell lines using CRISPR/Cas9 technology and show that miR-211 loss slowed growth and invasion in vitro, inhibited phosphoinositol-3-kinase signaling, and inhibited melanoma growth in vivo. miR-211 deficiency rendered melanoma cells metabolically vulnerable by attenuating mitochondrial respiration and tricarboxylic acid cycling. miR-211 was up-regulated by the BRAF inhibitor vemurafenib and in vemurafenib-resistant melanoma cells, with miR-211 loss rendering them more drug sensitive. miR-211 loss represents a "two-pronged" anticancer strategy by inhibiting both critical growth-promoting cell signaling pathways and rendering cells metabolically vulnerable, making it an extremely attractive and specific candidate combinatorial therapeutic target in melanoma.
| S-EPMC6309654 | biostudies-literature
Project description:Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to vemurafenib with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in vemurafenib-resistant cells was determined to impact vemurafenib response. Their expression was rapidly affected by vemurafenib treatment through RNA stabilization. Similar effects were elicited by MEK and ERK inhibitors but not AKT or Rac inhibitors. Ectopic expression of both miRNA in drug-naïve human melanoma cells was sufficient to confer vemurafenib resistance and more robust tumor growth in vivo Conversely, silencing their expression in resistant cells inhibited cell growth. Joint overexpression of miR-204-5p and miR-211-5p durably stimulated Ras and MAPK upregulation after vemurafenib exposure. Overall, our findings show how upregulation of miR-204-5p and miR-211-5p following vemurafenib treatment enables the emergence of resistance, with potential implications for mechanism-based strategies to improve vemurafenib responses.Significance: Identification of miRNAs that enable resistance to BRAF inhibitors in melanoma suggests a mechanism-based strategy to limit resistance and improve clinical outcomes. Cancer Res; 78(4); 1017-30. ©2017 AACR.
| S-EPMC5815895 | biostudies-literature
Project description:Loss of expression of surface antigens represents a significant problem for cancer immunotherapy. Microphthalmia-associated transcription factor (MITF-M) regulates melanocyte fate by driving expression of many differentiation genes, whose protein products can be recognized by cytolytic T lymphocytes. We previously reported that interleukin-1ß (IL-1ß) can downregulate MITF-M levels. Here we show that downregulation of MITF-M expression by IL-1ß was paralleled by an upregulation of miR-155 expression in four melanoma lines. We confirmed that miR-155 was able to target endogenous MITF-M in melanoma cells and demonstrated a role for miR-155 in the IL-1ß-induced repression of MITF-M by using an antagomiR. Notably, we also observed a strong negative correlation between MITF-M and miR-155 levels in a mouse model of melanoma. Taken together, our results indicate that MITF-M downregulation by inflammatory stimuli might be partly due to miR-155 upregulation. This could represent a novel mechanism of melanoma immune escape in an inflammatory microenvironment.
| S-EPMC4390329 | biostudies-literature
Project description:Microphthalmia-associated transcription factor (MITF) regulates normal melanocyte development and is also a lineage-selective oncogene implicated in melanoma and clear-cell sarcoma (i.e., melanoma of soft parts). We have observed that MITF expression is potently reduced under hypoxic conditions in primary melanocytes and melanoma and clear cell sarcoma cells through hypoxia inducible factor 1 (HIF1)-mediated induction of the transcriptional repressor differentially expressed in chondrocytes protein 1 (DEC1) (BHLHE40), which subsequently binds and suppresses the promoter of M-MITF (melanocyte-restricted MITF isoform). Correspondingly, hypoxic conditions or HIF1? stabilization achieved by using small-molecule prolyl-hydroxylase inhibitors reduced M-MITF expression, leading to melanoma cell growth arrest that was rescued by ectopic expression of M-MITF in vitro. Prolyl hydroxylase inhibition also potently suppressed melanoma growth in a mouse xenograft model. These studies illuminate a physiologic hypoxia response in pigment cells leading to M-MITF suppression, one that suggests a potential survival advantage mechanism for MITF amplification in metastatic melanoma and offers a small-molecule strategy for suppression of the MITF oncogene in vivo.
| S-EPMC3203758 | biostudies-literature
Project description:BackgroundIn recent years, microRNA-211 (miR211) has been considered as a tumor suppressor in multiple malignancies. However, the function of miR211 in human osteosarcoma has not been explored intensively so far. In this study, the relationship between miR211 and EZRIN was analyzed in human osteosarcoma.MethodsThe expression levels of miR211 and EZRIN were measured in both human osteosarcoma cells and tissues. The direct regulatory relationship between miR211 and EZRIN was evaluated using dual-luciferase assay. The effect of miR211 and EZRIN overexpression on cell proliferation, migration/invasion, and apoptosis was detected.ResultsThe expression of miR211 was obviously lower in osteosarcoma tissues than paracancerous tissues. EZRIN was identified as the direct target of miR211, and up-regulation of miR211 increased the percentage of cell apoptosis, and suppressed cell proliferation as well as cell migration/invasion via directly regulating EZRIN.ConclusionsOur study indicated that miR211 has an important role in the development and progress of osteosarcoma, and it might become a novel target in the diagnosis and treatment of human osteosarcoma.
| S-EPMC6617937 | biostudies-literature
Project description:While invasion and metastasis of tumour cells are the principle factor responsible for cancer related deaths, the mechanisms governing the process remain poorly defined. Moreover, phenotypic divergence of sub-populations of tumour cells is known to underpin alternative behaviors linked to tumour progression such as proliferation, survival and invasion. In the context of melanoma, heterogeneity between two transcription factors, BRN2 and MITF, has been associated with phenotypic switching between predominantly invasive and proliferative behaviors respectively. Epigenetic changes, in response to external cues, have been proposed to underpin this process, however the mechanism by which the phenotypic switch occurs is unclear. Here we report the identification of the NFIB transcription factor as a novel downstream effector of BRN2 function in melanoma cells linked to the migratory and invasive characteristics of these cells. Furthermore, the function of NFIB appears to drive an invasive phenotype through an epigenetic mechanism achieved via the upregulation of the polycomb group protein EZH2. A notable target of NFIB mediated up-regulation of EZH2 is decreased MITF expression, which further promotes a less proliferative, more invasive phenotype. Together our data reveal that NFIB has the ability to promote dynamic changes in the chromatin state of melanoma cells to facilitate migration, invasion and metastasis.
| S-EPMC5474438 | biostudies-literature
Project description:Melanoma tumors are highly heterogeneous, comprising of different cell types that vary in their potential for growth and invasion. Heterogeneous expression of the Microphthalmia-associated Transcription Factor (MITF) and the POU domain transcription factor BRN2 (POU3F2) has been found in malignant melanoma. Changing expression of these transcription factors as the disease progresses has been linked to the metastatic mechanism of phenotype switching. We therefore investigated the effects of MITF and BRN2 expression in melanoma growth and metastasis. Depletion of MITF resulted in a cell population that had a slowed cell cycle progression, was less invasive in vitro and had hindered tumor and metastasis forming ability in mouse xenograft studies. BRN2 depletion left a cell population with intact proliferation and invasion in vitro; however metastatic growth was significantly reduced in the mouse xenograft model. These results suggest that the proliferative population within melanoma tumors express MITF, and both MITF and BRN2 are important for metastatic growth in vivo. This finding highlights the importance of BRN2 and MITF expression in development of melanoma metastasis.
2017-08-16 | GSE101434 | GEO