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Skin cancer-associated S. aureus downregulates DNA repair mechanisms, and promotes oxidative stress and DNA damage in human keratinocytes

ABSTRACT: Actinic keratoses (AK) are premalignant lesions common on photo-damaged skin that, over time, can progress to squamous cell carcinoma (SCC). A high bacterial load of Staphylococcus aureus is associated with AK and SCC but it is unknown whether this has a direct impact on skin cancer development. To determine whether S. aureus is able to trigger pro-tumorigenic skin responses, we performed RNAseq and shotgun proteomics on primary human keratinocytes after challenge with sterile culture supernatant (‘secretome’) from S. aureus clinical strains isolated from AK and SCC. Certain S. aureus secretomes induced keratinocytes to overexpress SCC biomarkers that have been associated with skin carcinogenesis, and upregulate the expression of enzymes linked with reduced skin barrier function. Further, S. aureus secretomes downregulated DNA repair mechanisms and induced oxidative stress markers. Subsequent experiments confirmed that exposure to SCC-derived S. aureus secretomes lead to increased intracellular ROS levels and DNA damage in primary human keratinocytes. Altogether, this study reveal a novel mechanism for the pro-tumorigenic activity of S. aureus. Further studies are required to determine whether S. aureus products promote SCC development in vivo, which would have important implications for the treatment of AK and prevention of SCC.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Keratinocyte, Skin

SUBMITTER: Thomas Stoll

LAB HEAD: Michelle M. Hill

PROVIDER: PXD031622 | Pride | 2022-05-11

REPOSITORIES: Pride

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Skin cancer-associated S. aureus downregulates DNA repair mechanisms, and promotes oxidative stress and DNA damage in human keratinocytes

Project description:Actinic keratoses (AK) are premalignant lesions common on photo-damaged skin that, over time, can progress to squamous cell carcinoma (SCC). A high bacterial load of Staphylococcus aureus is associated with AK and SCC but it is unknown whether this has a direct impact on skin cancer development. To determine whether S. aureus is able to trigger pro-tumorigenic skin responses, we performed RNAseq and shotgun proteomics on primary human keratinocytes after challenge with sterile culture supernatant (‘secretome’) from S. aureus clinical strains isolated from AK and SCC. Certain S. aureus secretomes induced keratinocytes to overexpress SCC biomarkers that have been associated with skin carcinogenesis, and upregulate the expression of enzymes linked with reduced skin barrier function. Further, S. aureus secretomes downregulated DNA repair mechanisms and induced oxidative stress markers. Subsequent experiments confirmed that exposure to SCC-derived S. aureus secretomes lead to increased intracellular ROS levels and DNA damage in primary human keratinocytes. Altogether, this study reveal a novel mechanism for the pro-tumorigenic activity of S. aureus. Further studies are required to determine whether S. aureus products promote SCC development in vivo, which would have important implications for the treatment of AK and prevention of SCC.

2022-05-17 | PXD031676 | panorama

The ULK3 kinase is a key determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome

Project description:Epigenetic mechanisms oversee epidermal homeostasis and oncogenesis. The identification of kinases controlling these processes has direct therapeutic implications. We show that ULK3 is a nuclear kinase with elevated expression levels in squamous cell carcinomas (SCCs) arising in multiple body sites, including skin and Head/Neck. ULK3 loss by gene silencing or deletion reduces proliferation and clonogenicity of human keratinocytes and SCC-derived cells and affects transcription impinging on stem cell-related and metabolism programs. Mechanistically, ULK3 directly binds and regulates the activity of two histone arginine methyltransferases, PRMT1 and PRMT5 (PRMT1/5), with ULK3 loss compromising PRMT1/5 chromatin association to specific genes and overall methylation of histone H4, a shared target of these enzymes. These findings are of translational significance, as downmodulating ULK3 by RNA interference or locked antisense nucleic acids (LNAs) blunts the proliferation and tumorigenic potential of SCC cells and promotes differentiation in two orthotopic models of skin cancer.

2022-11-14 | MTBLS5155 | MetaboLights

Transcription profiling of human normal skin, actinic keratosis and squamous cell carcinoma

Project description:normal skin (no), actinic keratosis (ak), and squamous cell carcinoma (scc) of the skin were examined:; BACKGROUND: Carcinogenesis is a multi-step process indicated by several genes up- or down-regulated during tumor progression. This study examined and identified differentially expressed genes in cutaneous squamous cell carcinoma (SCC). RESULTS: Three different biopsies of 5 immunosuppressed organ-transplanted recipients each normal skin (all were pooled), actinic keratosis (AK) (two were pooled), and invasive SCC and additionally 5 normal skin tissues from immunocompetent patients were analyzed. Thus, total RNA of 15 specimens were used for hybridization with Affymetrix HG-U133A microarray technology containing 22,283 genes. Data analyses were performed by prediction analysis of microarrays using nearest shrunken centroids with the threshold 3.5 and ANOVA analysis was independently performed in order to identify differentially expressed genes (p < 0.05). Verification of 13 up- or down-regulated genes was performed by quantitative real-time reverse transcription (RT)-PCR and genes were additionally confirmed by sequencing. Broad coherent patterns in normal skin vs. AK and SCC were observed for 118 genes. CONCLUSION: The majority of identified differentially expressed genes in cutaneous SCC were previously not described.

2007-10-02 | E-GEOD-2503 | biostudies-arrayexpress

RNA-seq of human skin lesions diagnosed as actinic keratosis, intraepidermal carcinoma or squamous cell carcinoma

Project description:We report whole tissue RNA-seq data captured from 25 AK, IEC or SCC lesions obtained from the skin of 17 individuals. We used RNA-seq to detect and measure HPV E7 transcription.

2018-07-09 | E-MTAB-6430 | biostudies-arrayexpress

Novel Molecular Markers for non-melanoma skin cancer

Project description:normal skin (no), actinic keratosis (ak), and squamous cell carcinoma (scc) of the skin were examined: Carcinogenesis is a multi-step process indicated by several genes up- or down-regulated during tumor progression. The type and number of genes involved in non-melanoma skin cancer (NMSC) are still unclear. This study examined and identified different expressed genes in NMSC. Fifteen snap-frozen biopsies of five immunosuppressed organ-transplanted recipients each normal skin, actinic keratosis (AK) and invasive squamous cell carcinoma (SCC) were analysed. Total RNA was extracted reverse transcribed and biotin-labeled cRNA was used for hybridization with Affymetrix HG-U133A gene expression cDNA-microarrays containing 22,283 known genes. Confocal scanner evaluated the signals twice and data analysis was performed by predicition analysis of microarrays (PAM) using nearest shrunken centroids with the threshold 3.5 to identify genes best characterizing normal skin and skin cancer. ANOVA analysis was performed as a second independent method to identify differentially expressed genes (p<0.05, and p<0.15). Quantitative verification of 13 up- or down-regulated genes was performed by real-time RT-PCR and genes were confirmed by sequencing. Broad coherent patterns in normal skin vs. AK and SCC were observed for 118 genes. Some of the genes (e.g. annexin, lamin, and metalloproteinases) up-regulated in carcinomas in our study have previously reported as over-expressed in NMSC. In total 42 genes were up-regulated and 76 genes were down-regulated in non-melanoma skin cancer. The majority of genes identified have not been previously reported different expressed during non-melanoma skin carcinogenesis. Keywords: ordered

2006-06-30 | GSE2503 | GEO

A molecular signature for rejuvenation characterizes lesional and non lesional skin following Metvix treatment in Actinic Keratosis patients.

Project description:Actinic keratoses (AK) are proliferations of pre-neoplastic keratinocytes in the epidermis that are the result of cumulative ultraviolet (UV) radiations from sun exposure. Lesions are commonly found on sites of sun-exposed skin such as the face, balding scalp, and back of the hand. AKs may present on a patient as a few detectable lesions and 5-10% of them are susceptible to transform into SCC. In contrast, Organ Transplant Recipients (OTR) are of increasing risk at developing cancers as a consequence of long-term immunosuppressive therapy. The molecular changes that occur in lesional and perilesional skin of OTR patients 18 weeks following of PDT with topical MAL treatment were investigated to better understand the effect of the therapeutic intervention on the AK lesions. Our data show the complete normalization of the skin biology in the treated areas, i. e restoration of normal proliferation related gene profiles, and correction of aberrantly expressed cancer associated genes. We were also able to uncover a transcriptional signature of a rejuvenation effect induced by MAL-PDT in photodamaged skin opening new avenues in the use of PTD for treating photodamaged skin and field cancerized areas.

2018-06-15 | GSE90643 | GEO

Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cell types of origin

Project description:Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer type and arises from keratinocytes. Most cSCC progress from a UV-induced precancerous lesion termed actinic keratosis (AK). Despite various efforts to characterize these lesions molecularly, the etiology of AK and its progression to cSCC remain only partially understood. Here we have used Infinium MethylationEPIC BeadChips to interrogate the DNA methylation status of about 850.000 CpGs in epidermal preparations from healthy skin, AK and cSCC. Importantly, we found that the premalignant AK samples displayed classical features of cancer methylomes and were highly similar to cSCC methylomes. Further analysis identified typical features of stem cell methylomes, such as a reduced DNA methylation age, non-CpG methylation and stem cell-related keratin and enhancer methylation patterns. Interestingly, this signature was detected only in one half of the AK and cSCC samples, while the other half showed methylation patterns that were more closely related to the control epidermis. These findings suggest the existence of two distinct subclasses of AK and cSCC that originate from distinct keratinocyte differentiation stages.

2017-12-19 | E-MTAB-5738 | biostudies-arrayexpress

Effect of miR-939 overexpression on gene expression in heat-killed S. aureus-stimulated keratinocytes

Project description:Atopic dermatitis (AD) is a common, chronic inflammatory skin disease that seriously affects quality of life and is a major cause of skin diseases worldwide. Staphylococcus aureus (S. aureus) colonization on the skin plays an important role in the pathogenesis of AD; however, the mechanism of how it modulates skin immunity to exacerbate AD remains unclear. MicroRNAs are short non-coding RNAs that act as post-transcriptional regulators of genes. They are involved in the pathogenesis of various inflammatory skin diseases. In this study, we established miRNA expression profiles for keratinocytes stimulated with heat-killed S. aureus (HKSA). We found that miR-939 was highly upregulated in HKSA-stimulated keratinocytes and AD lesions. In vitro studies revealed that miR-939 increased the expression of matrix metalloproteinase genes, including MMP1, MMP3, and MMP9, as well as the cell adhesion molecule ICAM1 in human primary keratinocytes. In vivo studies indicated that miR-939 increased the expression of matrix metalloproteinases to promote the colonization of S. aureus and exacerbated S. aureus-induced AD-like skin inflammation. Taken together, these findings suggest that miR-939 is an important regulator of skin inflammation in AD.

2023-12-11 | GSE249837 | GEO

KGF effects on cutaneous SCC cells

Project description:Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. Gene expression profiling was performed of three cutaneous SCC cell lines treated with KGF (10 ng/ml) for 24 h, comparable untreated cells and of normal unterated epidermal keratinocytes to explore KGF-responce in SCC cells. Three cutanous SCC cell lines (established from two primary and one metastatic tumors) were cultured to 70% confluency, serum starved (0% FCS) for 16 h and treated with rKGF (10 ng/ml) for 24 h. Comparable cell cultures were left untreated with rKGF. Normal epidermal keratinocytes from two individuals were cultured in specified keratinocyte culture medium to 70% confluency. All cell cultures were processed for RNA extraction and Affymetrix whole transcript microarray gene expression analysis. Thus, the samples included three untreated cutaeous SCC cell lines (n=3), the same three cell lines treated with rKGF (n=3) and untreated epidermal keratinocytes from two individuals (n=2). Normal keratinocytes served as reference samples to untreated skin SCC cells.

2012-05-01 | E-GEOD-34652 | biostudies-arrayexpress

Functionally distinct cancer-associated fibroblast subpopulations establish a tumor-promoting environment in squamous cell carcinoma

Project description:Cutaneous squamous cell carcinoma (cSCC) is a serious public health problem due to its high incidence and metastatic potential. It may progress from actinic keratosis (AK), a precancerous lesion, or the in situ carcinoma Bowen's disease (BD). During this progression, malignant keratinocytes activate dermal fibroblasts into tumor-promoting cancer-associated fibroblasts (CAFs), whose origin and emergence remain largely unknown. Here, we generate and analyze >115,000 single-cell transcriptomes from healthy skin, BD and cSCC of male donors. Our results reveal immunoregulatory and matrix-remodeling CAF subtypes that might derive from pro-inflammatory and mesenchymal fibroblasts, respectively. These CAF subtypes are largely absent in AK and interact with different cell types to establish a pro-tumorigenic microenvironment. These findings are cSCC-specific and could not be recapitulated in basal cell carcinomas. Our study provides important insights into the functionalities of dermal CAFs that will be highly beneficial for the specific targeting of the cSCC microenvironment.

2023-08-09 | GSE218170 | GEO

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