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Interactions of melanoma cells with distal keratinocytes trigger metastasis via Notch signaling inhibition of MITF

ABSTRACT: The most critical stage in initiation of melanoma metastasis is the radial to vertical growth transition, yet the triggers of this transition remain elusive. We introduce a novel perspective, suggesting that the microenvironment drives melanoma metastasis independently of mutation acquisition. Here we examined the changes in microenvironment that occur during melanoma radial growth. We show that direct contact of melanoma cells with the remote epidermal layer triggers vertical invasion via Notch signaling activation, the latter serving to inhibit MITF function. Briefly, within the native Notch ligand-free microenvironment, MITF, the melanocyte lineage master regulator, binds and represses miR-222/221 promoter in an RBPJK-dependent manner. However, when radial growth brings melanoma cells into contact with distal differentiated keratinocytes that express Notch ligands, the activated Notch intracellular domain impairs MITF binding to miR-222/221 promoter. This de-repression of miR-222/221 expression triggers initiation of invasion. Our findings may direct novel prevention opportunities via targeting specific microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE69403 | GEO | 2015/07/30

SECONDARY ACCESSION(S): PRJNA285420

REPOSITORIES: GEO

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Interactions of melanoma cells with distal keratinocytes trigger metastasis via Notch signaling inhibition of MITF

Project description:The most critical stage in initiation of melanoma metastasis is the radial to vertical growth transition, yet the triggers of this transition remain elusive. We introduce a novel perspective, suggesting that the microenvironment drives melanoma metastasis independently of mutation acquisition. Here we examined the changes in microenvironment that occur during melanoma radial growth. We show that direct contact of melanoma cells with the remote epidermal layer triggers vertical invasion via Notch signaling activation, the latter serving to inhibit MITF function. Briefly, within the native Notch ligand-free microenvironment, MITF, the melanocyte lineage master regulator, binds and represses miR-222/221 promoter in an RBPJK-dependent manner. However, when radial growth brings melanoma cells into contact with distal differentiated keratinocytes that express Notch ligands, the activated Notch intracellular domain impairs MITF binding to miR-222/221 promoter. This de-repression of miR-222/221 expression triggers initiation of invasion. Our findings may direct novel prevention opportunities via targeting specific microenvironment. Two replicates of Notch-activated cells that were seeded on Delta-like-1 (DLL1) (2 ng/µl ) coated plates were compared to two replicates of cells without Notch activation. The goal of this experiment is to evaluate the changes of miRs expression in melanoma cells upon Notch signaling activation.

2015-07-30 | E-GEOD-69403 | biostudies-arrayexpress

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mRNA Breast Cancer Cell Line Profiles

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miR-221/222 drive synovial fibroblast expansion and pathogenesis of TNF-mediated arthritis

Project description:MicroRNAs (miRNAs) constitute fine tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA), however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. We have shown in the past that the expression of the miR-221/222 cluster is upregulated in RA SFs. Here, we demonstrate that miR-221/222 activation is downstream of major inflammatory cytokines, such as TNF and IL-1β, which promote miR-221/222 expression independently. miR-221/222 expression in SFs from the huTNFtg mouse model of arthritis correlates with disease progression. Targeted transgenic overexpression of miR-221/222 in SFs of the huTNFtg mouse model led to further expansion of synovial fibroblasts and disease exacerbation. miR-221/222 overexpression altered the transcriptional profile of SFs igniting pathways involved in cell cycle progression and ECM regulation. Validated targets of miR-221/222 included p27 and p57 cell cycle inhibitors, as well as Smarca1 (a chromatin remodeling component). In contrast, complete genetic ablation of miR-221/222 in arthritic mice led to decreased proliferation of fibroblasts, reduced synovial expansion and attenuated disease. scATAC-seq data analysis revealed increased miR-221/222 gene activity in the pathogenic and activated clusters of the intermediate and lining compartment. Taken together, our results establish an SF-specific pathogenic role of the miR-221/222 cluster in arthritis and suggest that its therapeutic targeting in specific subpopulations should inform the design of novel fibroblast-targeted therapies for human disease.

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Identification of genes differentially expressed in lung cancer cells after the transfection of miR-221 or miR-222.

Project description:To evaluate involvement of miR-221 and miR-222 in lung cancer, we investigated the effects of miR-221 and miR-222 overexpression on six lung cancer cell lines as well as one immortalized normal human bronchial epithelial cell line. Two cell lines, H3255 and H1299 with no replicates were studied. Cells were transfected with miR-221, miR-222, or miR control. Microarray analysis was done to identify genes differentially expressed in lung cancer cells after the transfection of miR-221 or miR-222.

2015-05-22 | E-GEOD-57676 | biostudies-arrayexpress

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Project description:Full title: Expression data from antisense miRNA-221/222 (si221/222) and control inhibitor (GFP) treated fulvestrant-resistant breast cancer cells The expression of miR-221/222 were found to be upregulated in fulvestrant resistant breast cancer cells MCF7-FR compared to its drug-sensitive counterpart MCF7. To investigate the role of miR-221/222 in acquired resistance to fulvestrant, we lowered the level of miR-221/222 in MCF7-FR cells using miRNA inhibitors (antagomirs), and compared gene expression profiles before and after treatment.

2011-01-29 | GSE19777 | GEO

Identification of genes differentially expressed in lung cancer cells after the transfection of miR-221 or miR-222.

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Gene expression profiling of MCF10A (miR-221/222 vs control)

Project description:Analysis of gene expression of MCF10A to identify the targets of miR-221 and miR-222 Keywords: MCF10, miR-221, miR-222 RNA profiles of human MCF10A cell line

2011-06-14 | E-GEOD-29327 | biostudies-arrayexpress

Transcription profiling of human breast cancer cell line profiles

Project description:mRNA breast cancer cell lines were profiled to study the function of hsa-mir-221 and hsa-mir-222. MCF7 cell lines were profiled after treatment with mir-221/222 mimics, and compared to profiles with transfection controls. Similarly, MDA-MB-231 cell lines were profiled after treatment with mir-221/222 inhibitors, and compared to profiles with transfection controls. Since ESR1 is a predicted target of mir-221/222 we also profiled MCF7 cell lines after disrupting ESR1 with an siRNA. Other breast cancer cell lines are provided because all cell lines were normalized together. Experiment Overall Design: mRNA breast cancer cell line profiles with some samples in duplicate or triplicate. See summary for more information.

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