Targeting the lineage-specific long non-coding RNA LINC01212 as an effective anti-melanoma therapeutic strategy
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PXD002565
ORGANISM(S): Homo sapiens
PROVIDER: GSE70180 | GEO | 2016/01/15
SECONDARY ACCESSION(S): PRJNA287799
REPOSITORIES: GEO
Similar Datasets
Project description:Focal amplifications of 3p13-3p14 occur in about 10% of melanoma and are associated with poor prognosis. The melanoma-specific oncogene MITF resides at the epicenter of this amplicon1. However, whether other loci present in this amplicon also contribute to melanomagenesis is unknown. Here we show that the recently annotated long non-coding RNA gene LINC01212 is consistently co-gained with MITF. In addition to being amplified, LINC01212 is a target of the lineage-specific transcription factor SOX10 and, consequently, it is expressed in more than 90% of human melanomas, but not in normal adult tissues. Whereas exogenous LINC01212 functions in trans to increase melanoma clonogenic potential LINC01212 knock-down dramatically decreases the viability of melanoma cells irrespective of their transcriptional cell state, BRAF, NRAS or TP53 status, diminishes melanoma growth and increases their sensitivity to MAPK-targeting therapeutics both in vitro and in patient-derived melanoma xenograft mouse models. Mechanistically, LINC01212 functions as a lineage addiction oncogene by interacting with and modulating the cellular localization and function of two proteins, XRN2 and p32, involved in nucleolar and mitochondrial rRNA processing, ribosome biogenesis and protein synthesis. LINC01212 targeting, especially in combination with BRAFV600E-inhibitors, is expected to deliver highly effective and tissue-restricted antimelanoma therapeutic responses. Five GapmeR3 treated and four control treated patient derived xenografts were analysed.
2016-01-15 | E-GEOD-70177 | biostudies-arrayexpress
Project description:Focal amplifications of 3p13-3p14 occur in about 10% of melanoma and are associated with poor prognosis. The melanoma-specific oncogene MITF resides at the epicenter of this amplicon1 . However, whether other loci present in this amplicon also contribute to melanomagenesis is unknown. Here we show that the recently annotated long non-coding RNA gene LINC01212 is consistently cogained with MITF. In addition to being amplified, LINC01212 is a target of the lineage-specific transcription factor SOX10 and, consequently, it is expressed in more than 90% of human melanomas, but not in normal adult tissues. Whereas exogenous LINC01212 functions in trans to increase melanoma clonogenic potential, LINC01212 knock-down drastically decreases the viability of melanoma cells irrespective of their transcriptional cell state, BRAF, NRAS or TP53 status and increases their sensitivity to MAPK-targeting therapeutics both in vitro and in Patient-Derived Xenograft (PDX) models. Mechanistically, LINC01212 interacts with p32, a master regulator of mitochondrial homeostasis and metabolism, to increase its mitochondrial targeting and pro-oncogenic function. Our results indicate that targeting the lineage addiction oncogene LINC01212, especially in combination with BRAFV600Einhibitors, disrupts vital mitochondrial functions in a cancer-cell specific manner and is therefore expected to deliver highly effective and tissuerestricted anti-melanoma therapeutic responses.
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Project description:Focal amplifications of 3p13-3p14 occur in about 10% of melanoma and are associated with poor prognosis. The melanoma-specific oncogene MITF resides at the epicenter of this amplicon1. However, whether other loci present in this amplicon also contribute to melanomagenesis is unknown. Here we show that the recently annotated long non-coding RNA gene LINC01212 is consistently co-gained with MITF. In addition to being amplified, LINC01212 is a target of the lineage-specific transcription factor SOX10 and, consequently, it is expressed in more than 90% of human melanomas, but not in normal adult tissues. Whereas exogenous LINC01212 functions in trans to increase melanoma clonogenic potential LINC01212 knock-down dramatically decreases the viability of melanoma cells irrespective of their transcriptional cell state, BRAF, NRAS or TP53 status, diminishes melanoma growth and increases their sensitivity to MAPK-targeting therapeutics both in vitro and in patient-derived melanoma xenograft mouse models. Mechanistically, LINC01212 functions as a lineage addiction oncogene by interacting with and modulating the cellular localization and function of two proteins, XRN2 and p32, involved in nucleolar and mitochondrial rRNA processing, ribosome biogenesis and protein synthesis. LINC01212 targeting, especially in combination with BRAFV600E-inhibitors, is expected to deliver highly effective and tissue-restricted antimelanoma therapeutic responses.
2016-01-15 | GSE70177 | GEO
Project description:Focal amplifications of 3p13-3p14 occur in about 10% of melanoma and are associated with poor prognosis. The melanoma-specific oncogene MITF resides at the epicenter of this amplicon1. However, whether other loci present in this amplicon also contribute to melanomagenesis is unknown. Here we show that the recently annotated long non-coding RNA gene LINC01212 is consistently co-gained with MITF. In addition to being amplified, LINC01212 is a target of the lineage-specific transcription factor SOX10 and, consequently, it is expressed in more than 90% of human melanomas, but not in normal adult tissues. Whereas exogenous LINC01212 functions in trans to increase melanoma clonogenic potential LINC01212 knock-down dramatically decreases the viability of melanoma cells irrespective of their transcriptional cell state, BRAF, NRAS or TP53 status, diminishes melanoma growth and increases their sensitivity to MAPK-targeting therapeutics both in vitro and in patient-derived melanoma xenograft mouse models. Mechanistically, LINC01212 functions as a lineage addiction oncogene by interacting with and modulating the cellular localization and function of two proteins, XRN2 and p32, involved in nucleolar and mitochondrial rRNA processing, ribosome biogenesis and protein synthesis. LINC01212 targeting, especially in combination with BRAFV600E-inhibitors, is expected to deliver highly effective and tissue-restricted antimelanoma therapeutic responses.
2016-01-15 | GSE70176 | GEO
Project description:Targeting the lineage-specific long non-coding RNA LINC01212 as an effective anti-melanoma therapeutic strategy
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Project description:Melanoma is the most lethal skin cancer, with increasing incidence worldwide. The molecular events that drive melanoma development and progression have been extensively studied, resulting in significant improvements in diagnostics and therapeutic approaches. However, a high drug resistance to targeted therapies and adverse effects of immunotherapies are still a major challenge in melanoma treatment. Therefore, the elucidation of molecular mechanisms of melanomagenesis and cancer response to treatment is of great importance. Recently, many studies have revealed the close association of long noncoding RNAs (lncRNAs) with the development of many cancers, including melanoma. These RNA molecules are able to regulate a plethora of crucial cellular processes including proliferation, differentiation, migration, invasion and apoptosis through diverse mechanisms, and even slight dysregulation of their expression may lead to tumorigenesis. lncRNAs are able to bind to protein complexes, DNA and RNAs, affecting their stability, activity, and localization. They can also regulate gene expression in the nucleus. Several functions of lncRNAs are context-dependent. This review summarizes current knowledge regarding the involvement of lncRNAs in melanoma. Their possible role as prognostic markers of melanoma response to treatment and in resistance to therapy is also discussed.
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Project description:BackgroundBreast cancer (BC) is considered to be one of the primary causes of cancer deaths in women. Cuproptosis was suggested to play an important role in tumor proliferation and tumor immune microenvironment. Therefore, an investigation was conducted to identify the relationship between cuproptosis-related long non-coding RNAs (lncRNAs) and BC prognosis.MethodBased on The Cancer Genome Atlas (TCGA), nine cuproptosis-related lncRNAs were identified by Pearson's analysis and Cox regression analysis to create a cuproptosis-related lncRNA signature. Subsequently, patients with BC were divided into high-risk and low-risk groups. The Kaplan-Meier curves and a time-dependent receiver operating characteristic (ROC) analysis were employed to elucidate the predictive capability of the signature. After that, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted by Gene Set Enrichment Analysis (GSEA), and the lncRNA-mRNA co-expression network was established by Cytoscape software. Furthermore, the ESTIMATE score was calculated, and the immune cell type component analysis was conducted. Eventually, immunotherapy response analysis was applied to identify the predictive power of cuproptosis-related lncRNAs to tumor immunotherapy response, including immune checkpoint gene expression levels, tumor mutational burden (TMB), and microsatellite instability (MSI).ResultsPatients with BC in the low-risk groups showed better clinical outcomes. The KEGG pathways in the high-risk groups were mainly enriched in immune response and immune cell activation. Furthermore, the ESTIMATE scores were higher in the low-risk groups, and their immune cell infiltrations were dramatically different from those of the high-risk groups. The low-risk groups were shown to have higher infiltration levels of CD8+ T cells and TMB-high status, resulting in better response to immunotherapies.ConclusionThe findings of this study revealed that the nine-cuproptosis-related lncRNA risk score was an independent prognostic factor for BC. This signature was a potential predictor for BC immunotherapy response. What we found will provide novel insight into immunotherapeutic treatment strategies in BC.
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