Analysis of p53 target genes in melanoma part 1
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE29359 | GEO | 2011/12/01
SECONDARY ACCESSION(S): PRJNA143001
REPOSITORIES: GEO
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Project description:Although mutations in p53 are infrequent in human melanoma, its function is abnormal. In this study, whole genome bead arrays were used to examine the expression of p53 target genes in extracts from 82 metastatic melanoma samples, compared to extracts derived from diploid human melanocytes, to provide a global assessment of aberrant p53 function. Total RNA extracted from 82 tumour samples and 8 melanocyte cell lines was analysed. Metastatic melanomas were compared to melanocyte cell lines.
2011-12-01 | E-GEOD-29359 | biostudies-arrayexpress
Project description:Although mutations in p53 are infrequent in human melanoma, its function is abnormal. In this study, whole genome bead arrays were used to examine the expression of p53 target genes in extracts from 6 melanoma cell lines, compared to extracts derived from diploid human melanocytes and fibroblasts, to provide a global assessment of aberrant p53 function. The expression of these genes was also examined in extracts derived from melanocytes and melanoma cell lines in which p53 expression had been inhibited using shRNA and compared to cells that had been transduced with a control shRNA.
2011-12-01 | GSE29361 | GEO
Project description:Although mutations in p53 are infrequent in human melanoma, its function is abnormal. In this study, whole genome bead arrays were used to examine the expression of p53 target genes in extracts from 6 melanoma cell lines, compared to extracts derived from diploid human melanocytes and fibroblasts, to provide a global assessment of aberrant p53 function. The expression of these genes was also examined in extracts derived from melanocytes and melanoma cell lines in which p53 expression had been inhibited using shRNA and compared to cells that had been transduced with a control shRNA. Total RNA extracted from 18 samples was analysed representing duplicates of 6 melanoma cell lines, 1 melanocyte cell line and 2 fibroblast cell lines. Melanoma cell lines were compared to normal cell lines. In addition, IgR3, Mel-RM and melanocyte cell lines were transduced with either control shRNA or p53 shRNA to evaluate the effect of p53 on its target genes. Cell lines transduced with control shRNA were compared to cell lines transduced with p53shRNA. Duplicates were analysed.
2011-12-01 | E-GEOD-29361 | biostudies-arrayexpress
Project description:Epigenetic alterations play significant roles in the melanoma tumorigenesis and malignant progression. We profiled genome-wide promoter DNA methylation patterns of melanoma cells deribed from primary lesions of Radial Growrth phase (RGP) and Vertical Growth Phase (VGP), metastatic lesions, and primary normal melanocytes by interrogating 14,495 genes using Illumina bead chip technology. By comparative analysis of the promoter methylation profiles, we identified epigenetically silenced gene signatures that potentially associated with malignant melanoma progression. Bisulphite converted genomic DNA from a group of melanoma cells representing pathologic stages of melanoma progression (3 cell lines derived from RGP melanoma lesions, 4 cell lines derived from VGP lesions, and 3 melastatic melanomas) and normal human primary melanocytes isolated from lightly pigmented adult skin were hybridized to Illumina's Infinium HumanMethylation27 BeadChips
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Project description:Epigenetic alterations play significant roles in the melanoma tumorigenesis and malignant progression. We profiled genome-wide promoter DNA methylation patterns of melanoma cells deribed from primary lesions of Radial Growrth phase (RGP) and Vertical Growth Phase (VGP), metastatic lesions, and primary normal melanocytes by interrogating 14,495 genes using Illumina bead chip technology. By comparative analysis of the promoter methylation profiles, we identified epigenetically silenced gene signatures that potentially associated with malignant melanoma progression.
2013-12-20 | GSE53516 | GEO
Project description:Enhanced fatty acid (FA) synthesis and uptake underpin the sustained membrane biogenesis and ATP production required for melanoma cell growth and division1-4. However, to thrive, melanoma cells must avoid a potential reduction in cell growth signalling, rampant reactive oxygen species (ROS) generation, and the build-up of toxic lipid species that can accompany excess free FA5. Here, we uncover and address the significance of frequent amplification and up-regulation of the Diacylglycerol O-acyltransferase 1 (DGAT1) gene in melanoma, whose encoded product catalyses the final step of Triacyglyceride (TAG) synthesis. Consistent with the classification of DGAT1 as an oncogene, we found that forced DGAT1 expression in p53 mutant zebrafish melanocytes was sufficient to induce melanoma, and accelerated melanoma progression initiated by co-expression of oncogenic BRAF or NRAS. Regarding DGAT1 function in human melanoma cells, its depletion, or alternatively pharmacological inhibition, suppressed mTOR-S6K signalling and increased levels of acyl carnitine species— FA derivatives that are the limiting substrate for FA oxidation (FAO). In turn, increased FAO induced mitochondrial malfunction, ROS generation, and lipid peroxidation. However, the resultant oxidative stress induced NRF2 and SESTRIN2 (SESN2) expression, which limited the extent of cell death. Conversely, DGAT1 over-expression enhanced mTOR-S6K signalling and cell growth, and protected against ROS, particularly in hypoxic conditions. Together, our data establish DGAT1 as a bona fide oncogene essential in melanoma cells for enabling FA accumulation.
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2016-05-13 | E-GEOD-79035 | biostudies-arrayexpress
Project description:The “cancerized field” concept posits that cells of a given tissue share a potentially oncogenic mutation or insult and are thus cancer-prone, yet only discreet clones within the field initiate tumor formation. In melanoma, tumors frequently (~50%) carry the oncogenic BRAFV600E mutation that is also nearly always present in benign nevi that rarely become melanoma. The zebrafish crestin gene is expressed embryonically in neural crest progenitors and is then specifically re-expressed in melanoma tumors. Here, we show by live imaging transgenic zebrafish crestin reporters that single melanocytes in a cancerized field with oncogenic BRAFV600E and p53 tumor suppressor loss undergo a change that recapitulates the neural crest progenitor (NCP) state, and patches of these cells initiate early melanoma. The crestin element is regulated by the NCP transcription factor sox10. Forced sox10 overexpression in melanocytes accelerated melanoma formation, consistent with reprogramming to the NCP state and activation of super-enhancers that lead to melanoma. Our work highlights the importance of the reemergence of the NCP state as a barrier to melanoma initiation.
2016-06-08 | GSE61825 | GEO
Project description:The “cancerized field” concept posits that cells of a given tissue share a potentially oncogenic mutation or insult and are thus cancer-prone, yet only discreet clones within the field initiate tumor formation. In melanoma, tumors frequently (~50%) carry the oncogenic BRAFV600E mutation that is also nearly always present in benign nevi that rarely become melanoma. The zebrafish crestin gene is expressed embryonically in neural crest progenitors and is then specifically re-expressed in melanoma tumors. Here, we show by live imaging transgenic zebrafish crestin reporters that single melanocytes in a cancerized field with oncogenic BRAFV600E and p53 tumor suppressor loss undergo a change that recapitulates the neural crest progenitor (NCP) state, and patches of these cells initiate early melanoma. The crestin element is regulated by the NCP transcription factor sox10. Forced sox10 overexpression in melanocytes accelerated melanoma formation, consistent with reprogramming to the NCP state and activation of super-enhancers that lead to melanoma. Our work highlights the importance of the reemergence of the NCP state as a barrier to melanoma initiation.
2016-06-08 | GSE61823 | GEO
Project description:The tumor suppressive miR-29 family of microRNAs is encoded by two clusters, miR-29b1~a and miR-29b2~c, and is regulated by several oncogenic and tumor suppressive stimuli. Here we investigated whether oncogenic MAPK hyperactivation regulates miR-29 abundance and how this signaling axis impacts melanoma development. Using mouse embryonic fibroblasts and human melanocytes, we found that oncogenic MAPK signaling stimulates p53-independent and p53-dependent transcription of pri-miR-29b1~a and pri-miR-29b2~c, respectively. Expression analyses revealed that while pri-miR-29a~b1 remains elevated, pri-miR-29b2~c levels decrease during melanoma progression. Using a rapid mouse modeling platform, we showed that inactivation of miR-29 in vivo accelerates the development of frank melanomas and decreases overall survival. We identified MAFG as a relevant miR-29 target that has oncogenic potential in melanocytes and is required for growth of melanoma cells. Our findings suggest that MAPK-driven miR-29 induction constitutes a tumor suppressive barrier by targeting MAFG, which is overcome by attenuation of miR-29b2~c expression.
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