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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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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. 5 different time points measured in triplicate comparing Dox-treated vs untreated c-FostetON keratinocytes

ORGANISM(S): Mus musculus

SUBMITTER: Marc Zapatka

PROVIDER: E-GEOD-50621 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression analyses of inducible c-Fos expressing kerationcytes

Project description: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.

2013-09-05 | GSE50621 | GEO

MMP10 degradomics in keratinocytes

Project description:Matrix metalloproteinases (MMPs) are important players in skin homeostasis, wound repair, and in the pathogenesis of skin cancer. One member – MMP10 – is specifically expressed in wound keratinocytes and in epithelial cancer cells, but its function is unclear and epidermal substrates are poorly characterized. To unravel the role of MMP10 in the skin, we employed Terminal Amine Isotopic Labeling of Substrates (TAILS), an iTRAQ-based quantitative proteomics technique for the discovery of protease substrates and their cleavage sites, to monitor MMP10-dependent proteolysis over time in secretomes from keratinocytes. By time-resolved abundance clustering of neo-N termini we revealed a cleavage site specificity preference of MMP10 for glutamate in the P1 position and identified the α6 integrin subunit, cysteine-rich angiogenic inducer 61 and dermokine as novel MMP10 substrates. Moreover, we confirmed the same MMP10-dependent processing of dermokine in vivo by TAILS analysis of epidermis from transgenic mice that overexpress a constitutively active mutant of MMP10 in basal keratinocytes. Since these substrates have been associated with cell adhesion, differentiation and senescence, MMP10 might contribute to modulation of these processes during skin repair.

2015-10-19 | PXD002474 | Pride

Transcription profiling of CHUK deleted mouse keratinocytes compared to wild type mouse keratinocytes

Project description:It has long been known that excessive mitotic activity due to H-Ras can block keratinocyte differentiation and cause skin cancer. It is not clear, however, whether there are any innate surveillants that ensure keratinocytes undergoing terminal differentiation, preventing the disease. IKKÎ± induces keratinocyte terminal differentiation and its reduction promotes skin tumor development. However, its nature function in skin cancer is unknown. Here we found that mice with IKKÎ± deletion in keratinocytes or in hair follicle keratinocytes developed a thickened epidermis and spontaneous squamous cell-like carcinomas. Inactivation of epidermal growth factor receptor (EGFR) or reintroduction of IKKÎ± inhibited excessive mitosis, induced terminal differentiation, and prevented skin cancer through an EGFR-driven autocrine loop in mice. Thus, IKKÎ± serves as an innate surveillant. Experiment Overall Design: The differences in gene expression profiles of CHUK deleted mouse keratinocytes compared to wild type mouse keratinocytes were analyzed using two dual-channel agilent microarrays in duplicates.

2009-08-12 | E-GEOD-12111 | biostudies-arrayexpress

Effect of HPV8-E7 expression on the secretome of keratinocytes

Project description:Human papillomavirus type 8 (HPV8) is associated with the development of non-melanoma skin cancer. In the past we already delved into the mechanisms involved in keratinocyte invasion, showing that the viral E7 oncoprotein is a key player that drives invasion of basal keratinocytes controlled by the extracellular protein fibronectin. To unravel further downstream effects in E7 expressing keratinocytes we now characterized alterations of the secretome of E7 expressing N/TERT keratinocytes.

2022-02-17 | PXD026100 | Pride

miR-146a effect in IFNg and TNFa induced keratinocytes

Project description:The aim of the study was to describe the function of miR-146a in human skin keratinocytes in relation to chronic skin diseases. miR-146a precursor and the control were transfected into human primary keratinocytes treated with IFN-gamma, TNF-alpha or left untreated. mRNA expression profiles of each conditions were detected.

2014-01-01 | E-MTAB-1739 | biostudies-arrayexpress

Expression data from mouse oral keratinocyte

Project description:Keratinocytes are the major constituent of epithelial cells at mucosal surfaces and skin, which cover organs, internal cavities and the body. Traditionally, keratinocytes have been considered as an inert component of the multilayered epithelium to protect the subepithelial compartments from the pathogenic microorganisms, toxic stimuli and physical trauma. However, accumulated researches of the airway, gastrointestinal tract and skin have demonstrated that keratinocytes function in the development of the immune system, promotion of pathologic inflammation and even impose diverse decisions on immune cells. We used microarrays to detail the global gene expression of oral keratinocyte during oral adaptive immune response. Oral keratinocyte were collected at three time points (control, 48h and 96h) in oral adaptive immune response for RNA extraction and hybridization on Affymetrix microarrays

2011-03-19 | E-GEOD-28035 | biostudies-arrayexpress

Autocrine IL-1α mediates NF-κB activation by oncogenic ras in keratinocytes

Project description:Constitutively active RAS plays a central role in the development of skin cancer in the classical two stage skin carcinogenesis in mice and in a number of human cancers. Ras-mediated tumor formation is commonly associated with upregulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. MyD88 is a crucial intermediate in the expression of multiple innate immune responders through signaling from the Toll-like/IL-1R family. We report that mice ablated for MyD88 or the IL-1R are resistant to topical skin carcinogenesis, and cultured MyD88-/- keratinocytes transduced with an oncogenic ras vector form only a few small tumors in orthotopic grafts. Initiated keratinocytes arising from oncogenic activation of ras are hyperproliferative but also resist signals for induced differentiation and upregulate a host of pro-inflammatory genes. Ras-transduced MyD88-/- keratinocytes are also hyperproliferative but the differentiation response is intact and pro-inflammatory genes are not upregulated. Using both genetic and pharmacological approaches, we find that in keratinocytes, the differentiation and immune regulation functions mediated by oncogenic ras require the establishment of an autocrine loop through IL-1α and its receptor leading to NF-κB activation. In the absence of MyD88 or IL-1R, this loop cannot be established. Further, blocking the IL-1a mediated NF-κB activation in ras-transduced wildtype keratinocytes corrects the defect in both differentiation response and proinflammatory gene expression. Collectively, these results demonstrate that ras activation converts normal keratinocytes to an initiated phenotype through a series of potentially reversible feedback signals that provide therapeutic opportunities through inhibition of IL-1 signaling. Gene expression comparison of wild type ras-transformed keratinocytes untreated (n=3) or treated (n=3) in vitro with the IL1R antagonist Anakinra.

2011-08-28 | E-GEOD-22777 | biostudies-arrayexpress

Effect of HPV8-E7 expression on the phospho-proteome in keratinocytes

2022-02-17 | PXD026099 | Pride

RNA-seq of IL-4 stimulated human keratinocytes

Project description:In this study we aim to determine the role of IL-4/STAT6 in gene expression in human keratinocytes using RNA-sequencing approach. Human keratinocytes were cultured for 2 or 5 days with calcium chloride to induce terminal differentiation as determined by the expression of epidermal differentiation complex genes. The cells were then stimulated with IL-4 for 3 and 24 hours, or along the 5 days culture period. We observed that IL-4 inhibits fully differentiation of keratinocytes, induces genes involved with production of inflammatory mediators, and reduces the healing capacity of human keratinocytes. Moreover, STAT6 controlled important genes involved with calcium binding, inflammation and epidermis development. Human keratinocytes were differentiated with calcium chloride for 2 days and incubated with media alone or 20ng/ml of recombinant human IL-4 for 3 and 24 hours. Human keratinocytes were differentiated with calcium chloride for 5 days with or wihout recombinant human IL-4 (20ng/ml). Keratinocytes transfected with control or STAT6 siRNA were differentiated with calcium chloride for 2 days and then stimulated with recombinant huma IL-4 for 24 hours.

2015-12-15 | E-GEOD-59275 | biostudies-arrayexpress

Hypoxia reveals the new function of Foxn1 in keratinocytes antioxidant defense system

Project description:Skin exposed to environmental threats including injuries and oxidative stress developed an efficient but not fully recognized systems of repair and antioxidant protection. In this project we provide evidence that Foxn1 in keratinocytes regulates elements of electron transport chain and participates in thioredoxin system (Txn2, Txnrd3, Srxn1) induction, particularly under hypoxic environment. It is shown that Foxn1 in keratinocytes upregulate glutathione thioredoxin reductase 3 (Txnrd3) protein, and high levels of Txnrd3 mRNA were detected in injured skin of Foxn1+/+ mice. It also shown that Foxn1 strongly downregulate CCN2 protein participating in reconstruction of the epidermis after injury. As in vitro assay revealed that Foxn1 controls keratinocytes migration stimulating it under normoxia and suppressing under hypoxia. Keratinocytes overexpressing Foxn1 and exposed to hypoxia showed reduced ability to promote angiogenesis by downregulation of Vegfa. In conclusion, this study showed a new mechanism in which Foxn1, along with hypoxia, participates in the activation of antioxidant defense and controls functional properties of keratinocytes.

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