NELFCD: A Crucial Factor in Uveal Melanoma Cell Proliferation and Tumorigenesis
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PROVIDER: PRJNA1204924 | ENA |
REPOSITORIES: ENA
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Project description:Uveal melanoma is the most common intraocular malignant tumour in adults.Posterior uveal melanoma is highly likely to metastasise to the liver (89%), lungs (29%), bone (17%), skin and subcutaneous tissues (12%), and lymph nodes (11%) and has an extremely high mortality rate.Due to the unclear pathogenesis, there is still no effective treatment for uveal melanoma other than surgery.Thus, it is crucial to investigate the mechanisms of carcinogenesis and proliferation of uveal melanoma.Recent evidence suggests that biomolecular condensates，membrane-free cellular compartments formed by liquid-liquid phase separation (LLPS), plays crucial roles in physiological and tumorigenic processes.The aim of this study was to investigate the role of LLPS in the development of uveal melanoma in order to explore potential therapeutic targets for UM.
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Project description:Uveal melanoma is the most common primary intraocular neoplasm, arising from melanocytes of the choroid plexus, ciliary body, and iris of the eye. The mechanism of tumorigenesis in uveal melanoma still remains unclear, resulting in poor outcomes of systemic therapies available for the treatment of uveal melanoma. Currently, ADP-ribosylation factor-like 4C (ARL4C), an ARF-Like small GTP-binding protein, has been confirmed to be closely involved in the occurrence of various tumors, including colorectal, lung, liver, gastric and ovarian cancers as well as glioblastoma. Here, we found that ARL4C was strongly expressed in uveal melanoma cells and widely distributed in the cytosol and nucleus. The proliferation and metastasis capabilities of OCM-1 and 92-1 uveal melanoma cells were significantly decreased after ARL4C knockdown both in vitro and in vivo. Furthermore, over-expression of ARL4C in ARL4C-depleted cells can significantly rescue the abilities of proliferation and metastasis in above both cells. In addition, direct injection of ARL4C small interfering RNA (siRNA) into OCM-1 cell-derived tumors inhibited tumor growth in immunodeficient mice. Therefore, ARL4C tightly participates in tumorigenesis and might represent a novel therapeutic target to uveal melanoma. We believe that small molecule drugs targeting ARL4C could be explored and further applied to clinical therapy of uveal melanoma in years or decades to come.
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Project description:Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a genome-wide CRISPR-Cas9 knockout screen, which revealed the LKB1-SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and up-regulation of the sodium/calcium (Na+/Ca2+) exchanger SLC8A1. This signalling cascade promotes increased level of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria-targeted antioxidant promotes enhanced cell death efficacy in LKB1- and SIK2-negative uveal melanoma cells compared to control cells. We also designed an LKB1-deficient prognostic gene signature of patient survival that may be predictive of response to this combination. Our data thus identify not only metabolic vulnerabilities, but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma.
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Project description:G protein alpha q and 11 are mutated in 90% of uveal melanoma and they activate the MAPK pathway. Using expression microarray analysis, we identified a unique MEK dependent transcriptional signature with genes that are involved in proliferation and tumor cell invasion. Uveal melanoma cells were profiled on Illumina Human HT-12 arrays per manufacturer's instructions
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Project description:Genome wide DNA methylation profiling of primary uveal melanoma cells, normal uveal melanocytes, neural crest stem cells, embryonic stem cells and uveal melanoma cell lines. The Illumina Infinium 27k Human DNA methylation Beadchip Rev B was used to obtain DNA methylation profiles across approximately 27,000 CpGs in the samples. Samples included 58 primary UM, 3 NUM and NCSC controls and 2 cell lines. Bisulphite converted DNA from the 63 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip Rev B
2013-02-14 | E-GEOD-44296 | biostudies-arrayexpress
Project description:Despite advances in surgery and radiotherapy of uveal melanoma (UM), many patients develop distant metastases that poorly respond to therapy. Improved therapies for the metastatic disease are therefore urgently needed. Expression of the epidermal growth factor receptor (EGFR), a target of kinase inhibitors and humanized antibodies in use for several cancers, had been reported. 48 human UMs were analyzed by expression profiling. Evidence for signaling in tumors was obtained through the application of a UM-specific EGF signature. The EGFR specific kinase inhibitor, Gefitinib, and the humanized monoclonal antibody, Cetuximab, were tested for their effect on EGFR signaling. Natural killer cell mediated antibody-dependent cellular cytotoxicity (ADCC) and TNF-alpha release was analyzed for Cetuximab. EGFR appears suited as a novel molecular drug target for therapy of uveal melanoma. Gene expression profiles of 19 unique samples from uveal melanoma patients were measured.
2013-11-18 | E-GEOD-51880 | biostudies-arrayexpress
Project description:G protein alpha q and 11 are mutated in 80% of uveal melanoma. We observed that treatment with the BRD4 inhibitor JQ1 resulted in different phenotypic responses in G-protein mutant uveal melanoma cell lines and wild type uveal melanoma cell lines. We used microarrarys to profile the gene expression changes occuring in wild type and mutant cell lines in response to treament with JQ1 Uveal melanoma cells were profiled in triplicate on Affymetrix Human Genome U133A 2.0 Array arrays per manufacturer's instructions
2015-02-19 | E-GEOD-66048 | biostudies-arrayexpress
Project description:Chromosome 3p monosomy is associated with a poor clinical outcome of patients with uveal melanoma. Since a copy of the tumor suppressor miR-16 gene is lost for these patients, we postulated that a 3p loss may reduce the miR-16 amount and activity, promoting RNA derepression and tumor burden (loss of brake effect) as observed in chronic lymphocytic leukemia. Unexpectedly, we found that miR-16 expression level is not decreased despite the 3p monosomy. In contrast, our results suggested that miR-16 activity is impaired in uveal melanoma. Here, we investigated the molecular mechanism explaining the sequestration of miR-16 by RNAs. By defining the miR-16 interactome, two genes sets have been highlighted, suggesting two divergent miR-16 functions. In addition to the canonical miR-16 targets such as CCND3 and CDC25A, we identified another set of miR-16-interacting RNAs called thereafter miR-16 sponges. miR-16 binds to these RNAs sponge without inducing their decay. Mechanistically, the miR-16/RNA non-canonical base-pairing promoted stability of mRNAs involved in cancer cell proliferation. The biological relevance has been challenged in uveal melanoma. We showed that patients with poor overall survival expressed higher levels of miR-16 sponges and canonical miR-16 targets. These results strongly suggested that miR-16 is no longer able to repress its targets and, in contrast, promotes RNA stability and protein expression of oncogenes. miR-16 activity assessment using our Sponge-signature discriminates the patient’s overall survival as efficiently as the current method based on copy number variations and driver mutations detection. To conclude, miRNA loss of function due to miRNA sequestration seems to promote cancer burden by two combined events – 'loss of brake and an acceleration'. Our results highlight the oncogenic role of the non-canonical base-pairing between miRNAs/mRNAs in uveal melanoma.
2022-10-04 | E-MTAB-10940 | biostudies-arrayexpress
Project description:Gene expression in primary uveal melanoma cells and normal cell controls The HumanHT-12 v3 gene expression microarray (Illumina) was used to analyze RNA isolated from snap-frozen primary uveal melanoma tissue isolated from enucleated eyes and from normal cell controls.
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