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TRANSCRIPTIONAL EFFECTS OF INHIBITING EGFR IN KERATINOCYTES

ABSTRACT: EGFR activation is important in human epithelial malignancies, including cutaneous squamous cell carcinoma, lung, colon, pancreatic and other cancers. Therapies targeting EGFR are currently used to treat such cancers, but one significant drawback to EGFR inhibitor therapies is the associated skin toxicity. This toxicity usually presents as papular or pustular folliculitis, dry skin with pruritus and hair and nails abnormalities. The side effects often limit the usefulness of EGFR inhibitors in cancer treatment. The transcriptional changes caused by EGFR inhibition in epidermal keratinocytes have not been extensively explored. To define the transcriptional changes caused by inhibition of EGFR in primary human epidermal keratinocytes, we treated these cells with Tyrphostin and compared treated and control cultures in parallel, using Affymetrix microarrays. Using metaanalysis approaches, we integrated the observed changes with a large set of already existing data on transcriptional profiling in epidermal keratinocytes. We found that EGFR inhibition suppresses expression of genes associated with keratinocyte proliferation, attachment and motility. Apoptosis is facilitated by both induction of proapoptotic and suppression of antiapoptotic genes. Surprisingly, EGFR inhibition induces expression of markers of epidermal differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE41680 | GEO | 2012/10/19

SECONDARY ACCESSION(S): PRJNA177919

REPOSITORIES: GEO

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TRANSCRIPTIONAL EFFECTS OF INHIBITING EGFR IN KERATINOCYTES

Project description:EGFR activation is important in human epithelial malignancies, including cutaneous squamous cell carcinoma, lung, colon, pancreatic and other cancers. Therapies targeting EGFR are currently used to treat such cancers, but one significant drawback to EGFR inhibitor therapies is the associated skin toxicity. This toxicity usually presents as papular or pustular folliculitis, dry skin with pruritus and hair and nails abnormalities. The side effects often limit the usefulness of EGFR inhibitors in cancer treatment. The transcriptional changes caused by EGFR inhibition in epidermal keratinocytes have not been extensively explored. To define the transcriptional changes caused by inhibition of EGFR in primary human epidermal keratinocytes, we treated these cells with Tyrphostin and compared treated and control cultures in parallel, using Affymetrix microarrays. Using metaanalysis approaches, we integrated the observed changes with a large set of already existing data on transcriptional profiling in epidermal keratinocytes. We found that EGFR inhibition suppresses expression of genes associated with keratinocyte proliferation, attachment and motility. Apoptosis is facilitated by both induction of proapoptotic and suppression of antiapoptotic genes. Surprisingly, EGFR inhibition induces expression of markers of epidermal differentiation. Time course of human epidermal keratinocytes treated with Tyrphostin (AG1478) and untreated controls

2012-10-19 | E-GEOD-41680 | biostudies-arrayexpress

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

EGFR and hair shaft differentiation

Project description:EGFR signaling controls skin development and homeostasis in mice and humans and its deficiency causes severe skin inflammation, which might affect epidermal stem cell behaviour. Here, we describe the inflammation-independent effects of EGFR-deficiency during skin morphogenesis and in adult HFSCs. Expression and alternative splicing analysis of RNAseq data from interfollicular epidermis and outer root sheath indicate that EGFR controls genes involved in epidermal differentiation, but also in centrosome function, DNA damage, cell cycle and apoptosis. Genetic experiments employing p53-deletion in EGFR–deficient epidermis reveal that EGFR signalling exhibits p53-dependent functions in proliferative epidermal compartments, as well as p53–independent functions in differentiated hair shaft keratinocytes. Loss of EGFR leads to absence of Lef1 protein specifically in the innermost epithelial hair layers, resulting in disorganization of medulla cells. Thus, our results uncover important spatial and temporal features of cell-autonomous EGFR functions in the epidermis.

2019-07-23 | GSE128436 | GEO

IKKα Is Required to Maintain Skin Homeostasis and Prevent Skin Cancer

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. IKKα 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 IKKα 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 IKKα inhibited excessive mitosis, induced terminal differentiation, and prevented skin cancer through an EGFR-driven autocrine loop in mice. Thus, IKKα serves as an innate surveillant.

2009-07-14 | GSE12111 | GEO

JNK1 Signaling Downstream of the EGFR Pathway Contributes to Imiquimod-induced Skin Inflammation (RNA-seq)

Project description:c-Jun N-terminal protein kinase 1 (JNK1) is involved in multiple biological processes but its implication in inflammatory skin diseases is still poorly defined. Herein, we studied the role of JNK1 in the context of imiquimod-induced skin inflammation. We observed that constitutive ablation of JNK1 reduced imiquimod-induced acanthosis and expression of inflammatory markers. Conditional deletion of JNK1 in myeloid cells led to reduced skin inflammation, a finding that was associated with impaired Aldara®-induced inflammasome activation in vitro. Next, we evaluated the specific role of JNK1 in epidermal cells. We observed a reduced imiquimod-induced acanthosis and keratinocytes proliferation despite similar levels of inflammatory markers. Transcriptomic and epigenomic analysis of keratinocytes revealed the potential involvement of JNK1 in the EGFR signaling pathway. Finally, we show that inhibition of the EGFR pathway reduced imiquimod-induced acanthosis. Taken together, these data indicate that JNK1 plays a dual role in the context of psoriasis by regulating the production of inflammatory cytokines by myeloid cells and the sensitivity of keratinocytes to EGFR ligands. These results suggest that JNK1 could represent a valuable therapeutic target in the context of psoriasis.

2021-01-12 | GSE164580 | GEO

JNK1 Signaling Downstream of the EGFR Pathway Contributes to Imiquimod-induced Skin Inflammation (ATAC-seq)

2021-01-12 | GSE164579 | GEO

Epidermal RelA specifically restricts contact allergen-induced inflammation and apoptosis in skin

Project description:Strong inhibition of NF-kB signaling in the epidermis results in spontaneous skin inflammation in mice and men. Since there is evidence for linkage between polymorphisms within the NF-kB signaling pathway and human inflammatory skin phenotypes, we asked whether partial functional inhibition of NF-kB signaling in epidermal keratinocytes can modulate clinically relevant skin inflammation. We therefore mutated rela specifically in the epidermis of mice (RelAE-MUT mice). These mice show no inflammatory phenotype. Induction of contact allergy, but not croton oil induced irritant dermatitis, resulted in stronger ear swelling and increased epidermal thickness in RelAE-MUT mice. Both contact allergen and croton oil treatment led to increase expression of calgranulins A and B (S100A8/ A9) in RelAE-MUT mice. Epidermal hyperproliferation in RelAE-MUT mice was non-cell autonomous since cultured primary epidermal keratinocytes from RelAE-MUT mice showed reduced proliferation compared to controls. These results demonstrate that epidermal RelA specifically regulates DTH-induced skin inflammation. In addition, we here describe an essential but non- specific function of RelA in the protection of epidermal keratinocytes from apoptosis. Our study identifies new functions of NF-kB signaling in the epidermis and corroborates a specific role of epidermal keratinocytes in the regulation of skin inflammation

2014-12-01 | GSE56067 | GEO

Conditional keratinocyte-specific ADAM17 knockout in mice alters skin homeostasis

Project description:This study investigates the role of ADAM17 (a disintegrin and metalloproteinase 17) in skin homeostasis. Here, we show that mice lacking ADAM17 in keratinocytes have a normal epidermal barrier and skin architecture at birth, but develop pronounced defects in epidermal barrier integrity soon after birth and chronic dermatitis as adults. The dysregulated expression of epidermal differentiation proteins becomes evident 2 days after birth, followed by transepidermal water loss and inflammatory immune cell infiltration. Our results identify a previously unappreciated critical role of the ADAM17/EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier.

2012-06-21 | GSE38830 | GEO

The Skin Barrier Defects Caused by Keratinocyte-Specific Deletion of ADAM17 or EGFR are Based on Highly Similar Proteome and Degradome Alterations

Project description:ADAM17 and EGFR are essential key players for epidermal integrity. Keratinocyte-specific deletion of ADAM17 in mice results in pronounced alterations in terminal differentiation of keratinocytes leading to severe epidermal barrier defects with enhanced transepidermal water loss. Thereby, mice deficient for ADAM17 in keratinocytes phenocopy mice with a keratinocyte-specific deletion of EGFR, highlighting the role of ADAM17 as a “ligand sheddase”, as it sheds membrane bound EGFR ligands from the cell surface and finally modulates EGFR signaling. In this study we aim for the first proteomic / degradomic approach to characterize the disruption of the ADAM17-EGFR signaling axis and its consequences for epidermal barrier formation. Proteomic profiling of the epidermal proteome of mice deficient for either ADAM17 or EGFR in keratinocytes at postnatal days 3 and 10 revealed highly similar protein alterations for ADAM17 and EGFR deficiency. These include massive proteome alterations of structural and regulatory components important for barrier formation, like transglutaminases, involucrin, S100 protein family members and S100 fused-type proteins, such as filaggrin, filaggrin-2 and hornerin. Cleavage site analysis using TAILS reveals, among other ADAM17 dependent cleavage sites, increased proteolytic processing of S100 fused-type proteins, including filaggrin-2. Alterations in proteolytic processing are supported by altered protein abundance of numerous proteases upon keratinocyte-specific Adam17 or Egfr deletion, among them kallikreins, cathepsins and their inhibitors. In addition, N-terminal proteomics indicated usage of alternative translation start sites. This study highlights the essential role of proteolytic processing for maintenance of a functional epidermal barrier. Furthermore it suggests that most defects in formation of the postnatal epidermal barrier upon keratinocyte-specific ADAM17 deletion are mediated via EGFR.

2016-04-20 | PXD002597 | Pride

Skin Toxicity in Patients With Metastatic Colorectal Cancer Treated With Anti-EGFR and Chemotherapy (DERMIA)

Project description:Clinical evidence has suggested that sub-antimicrobial doses of doxycycline may have the potential to treat inflammatory lesions of acne. The efficacy of doses below 100 mg/day of doxycycline in the prevention of skin toxicity in patients with treated with Epidermal Growth Factor Receptor (EGFR)-targeted therapies has never been studied. Therefore, the aim of the present study is to describe the efficacy of doxycycline 50 or 100 mg per day in the prevention of skin toxicity in patients with metastatic Colorectal cancer (mCRC) treated with anti-EGFR in combination with chemotherapy.

| 2267065 | ecrin-mdr-crc

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