Unknown,Transcriptomics,Genomics,Proteomics

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Differential gene expression by suppression of either SOX2 or TP63 in KYSE70 human esophageal squamous carcinoma cell line.

ABSTRACT: SOX2 is a transcription factor essential for pluripotent stem cells, and development and maintenance of squamous epithelium. We previously reported SOX2 an oncogene subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs)1. Here we demonstrate in SCCs that SOX2 interacts with another master squamous transcription factor p63, and through ChIP-seq show that genomic occupancy of SOX2 overlaps with that of p63 at a large number of loci and that they cooperatively regulate gene expression including ETV4, which we find essential for SOX2-amplified SCC cell survival. Furthermore, SOX2 binds to distinct genomic loci in SCCs than in embryonic stem cells and the SOX2-p63 coordinate binding is unique to SCC. In addition, a subset of SOX2 genomic binding sites in SCC that lack p63 co-occupancy are co-occupied by the AP-1 transcriptional complex. These demonstrate that SOX2M-bM-^@M-^Ys actions in SCC differ substantially from its role in pluripotency and identify novel SOX2 interactions that will enable deeper characterization of SOX2M-bM-^@M-^Ys function in SCC. KYSE70 cells with stable expression of either pLKO-Tet-Op-shSOX2 or pLKO-Tet-Op-shTp63 were treated with 50ng/ml of doxycyline for 4 days. Total RNA was extracted, polyA+ selected, reverse transcribed, library constructed and sequencing was performed with Illumina HiSeq 2000. Differencial gene expression between the stable cell lines with Dox-induced and non-Dox treated was analyzed to determine the effects by suppression of either SOX2 or TP63 in KYSE70 cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Shouyong Peng

PROVIDER: E-GEOD-47058 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Cancer stem cells (CSCs) have been reported in various cancers including skin squamous cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here, we found that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells (SCs), was the most upregulated transcription factor in CSCs of squamous skin tumours. Sox2 is absent in normal epidermis and begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which Sox2 is frequently genetically amplified, the expression of Sox2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis dramatically decreases skin tumour formation following chemical induced carcinogenesis. Using Sox2-GFP knockin mice, we showed that Sox2 expressing cells in invasive SCC are greatly enriched in tumour propagating cells (TPCs) that further increase upon serial transplantations. Lineage ablation of Sox2 expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of Sox2 expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to their regression and decreases their ability to be propagated upon transplantation into immunodeficient mice, supporting the essential role of Sox2 in regulating CSC functions. Transcriptional profiling of Sox2-GFP expressing CSC and upon Sox2 deletion uncovered a gene network regulated by Sox2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct Sox2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion, and paraneoplastic syndrome. Altogether, our study demonstrates that Sox2, by marking and regulating the functions of skin tumour initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours. We used microarrays to profile Sox2-GFP expressing CSC to uncover a gene network regulated by Sox2 in primary tumour cells in vivo. Two different biological replicates from SOX2-GFP+ and SOX2-GFP- TECs (control) from 2 different SCC from 2 different mice were analysed. Total RNA was analysed using Mouse whole genome 430 2.0 array from Affymetrix.

Project description:Cancer stem cells (CSCs) have been reported in various cancers including skin squamous cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here, we found that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells (SCs), was the most upregulated transcription factor in CSCs of squamous skin tumours. Sox2 is absent in normal epidermis and begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which Sox2 is frequently genetically amplified, the expression of Sox2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis dramatically decreases skin tumour formation following chemical induced carcinogenesis. Using Sox2-GFP knockin mice, we showed that Sox2 expressing cells in invasive SCC are greatly enriched in tumour propagating cells (TPCs) that further increase upon serial transplantations. Lineage ablation of Sox2 expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of Sox2 expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to their regression and decreases their ability to be propagated upon transplantation into immunodeficient mice, supporting the essential role of Sox2 in regulating CSC functions. Transcriptional profiling of Sox2-GFP expressing CSC and upon Sox2 deletion uncovered a gene network regulated by Sox2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct Sox2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion, and paraneoplastic syndrome. Altogether, our study demonstrates that Sox2, by marking and regulating the functions of skin tumour initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours. We used microarrays to profile tumour epithelial cells upon Sox2 deletion to uncover a gene network regulated by Sox2 in primary tumour cells in vivo. Microarray analysis was performed on FACS isolated Epcam+ a6+ TECs from 3 different biological experiments following TAM administration to K14CREER:SOX2fl/fl and control mice. Total RNA was analysed using Mouse whole genome 430 2.0 array from Affymetrix.

Project description:Cancer stem cells (CSCs) have been reported in various cancers including skin squamous cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here, we found that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells (SCs), was the most upregulated transcription factor in CSCs of squamous skin tumours. Sox2 is absent in normal epidermis and begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which Sox2 is frequently genetically amplified, the expression of Sox2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis dramatically decreases skin tumour formation following chemical induced carcinogenesis. Using Sox2-GFP knockin mice, we showed that Sox2 expressing cells in invasive SCC are greatly enriched in tumour propagating cells (TPCs) that further increase upon serial transplantations. Lineage ablation of Sox2 expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of Sox2 expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to their regression and decreases their ability to be propagated upon transplantation into immunodeficient mice, supporting the essential role of Sox2 in regulating CSC functions. Transcriptional profiling of Sox2-GFP expressing CSC and upon Sox2 deletion uncovered a gene network regulated by Sox2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct Sox2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion, and paraneoplastic syndrome. Altogether, our study demonstrates that Sox2, by marking and regulating the functions of skin tumour initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours. We used microarrays to profile tumour epithelial cells upon Sox2 deletion to uncover a gene network regulated by Sox2 in primary tumour cells in vivo.

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Differential gene expression by suppression of either SOX2 or TP63 in KYSE70 human esophageal squamous carcinoma cell line.

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