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Expression analyses of inducible c-Fos expressing kerationcytes

ABSTRACT: Expression analyses comparing c-Fos expressing keratinocytes vs non-expressing controls. Skin squamous cell carcinomas (SCCs) are the second most prevalent skin cancers. Chronic skin inflammation has been associated with the development of SCCs, but the contribution of skin inflammation to SCC development remains largely unknown. In this study we demonstrate that inducible expression of c-fos in the epidermis of adult mice is sufficient to promote inflammation-mediated epidermal hyperplasia leading to the development of pre-neoplastic lesions. Interestingly, c-Fos transcriptionally controls mmp10 and s100a7a15 expression in keratinocytes subsequently leading to CD4 T cell recruitment to the skin, thereby promoting epidermal hyperplasia. Combining inducible c-fos expression in the epidermis with a single dose of the carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA) leads to the development of highly invasive SCCs, which are prevented by using the anti-inflammatory drug Sulindac. Moreover, human SCCs display a correlation between c-FOS expression and elevated levels of MMP10 and S100A15 proteins as well as CD4 T cell infiltration. Our studies demonstrate a bidirectional crosstalk between pre-malignant keratinocytes and infiltrating CD4 T cells in SCC development. Therefore, targeting inflammation along with the newly identified targets, such as MMP10 and S100A15, represent promising therapeutic strategies to treat SCCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE50621 | GEO | 2013/09/05

SECONDARY ACCESSION(S): PRJNA218096

REPOSITORIES: GEO

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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.

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Expression analyses of inducible c-Fos expressing kerationcytes

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