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Deregulation of XPC and CypA by cyclosporin A: an immunosuppression-independent mechanism of skin carcinogenesis.

ABSTRACT: Skin cancer is the most common malignancy in organ transplant recipients, causing serious morbidity and mortality. Preventing and treating skin cancer in these individuals has been extraordinarily challenging. Following organ transplantation, cyclosporin A (CsA) has been used as an effective immunosuppressive to prevent rejection. Therefore immunosuppression has been widely assumed to be the major cause for increased skin carcinogenesis. However, the mechanism of skin carcinogenesis in organ transplant recipients has not been understood to date; specifically, it remains unknown whether these cancers are immunosuppression dependent or independent. Here, using both immunocompromised nude mice which are defective in mature T lymphocytes as an in vivo model and human keratinocytes as an in vitro model, we showed that CsA impairs genomic integrity in the response of keratinocytes to ultra violet B (UVB). Following UVB radiation, CsA inhibited UVB-induced DNA damage repair by suppressing the transcription of the DNA repair factor xeroderma pigmentosum C (XPC). In addition, CsA compromised the UVB-induced checkpoint function by upregulating the molecular chaperone protein cyclophilin A (CypA). XPC mRNA levels were lower, whereas CypA mRNA and protein levels were higher in human skin cancers than in normal skin. CsA-induced phosphoinositide 3-kinase(PI3K)/AKT activation was required for both XPC suppression and CypA upregulation. Blocking UVB damage or inhibiting the PI3K/AKT pathway prevented CsA-sensitized skin tumorigenesis. Our findings identified deregulation of XPC and CypA as key targets of CsA, and UVB damage and PI3K/AKT activation as two principal drivers for CsA-sensitized skin tumorigenesis, further supporting an immunosuppression-independent mechanism of CsA action on skin tumorigenesis.

SUBMITTER: Han W

PROVIDER: S-EPMC3435459 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Deregulation of XPC and CypA by cyclosporin A: an immunosuppression-independent mechanism of skin carcinogenesis.

Han Weinong W Soltani Keyoumars K Ming Mei M He Yu-Ying YY

Cancer prevention research (Philadelphia, Pa.) 20120730 9

Skin cancer is the most common malignancy in organ transplant recipients, causing serious morbidity and mortality. Preventing and treating skin cancer in these individuals has been extraordinarily challenging. Following organ transplantation, cyclosporin A (CsA) has been used as an effective immunosuppressive to prevent rejection. Therefore immunosuppression has been widely assumed to be the major cause for increased skin carcinogenesis. However, the mechanism of skin carcinogenesis in organ tra ...[more]

PMID: 22846842

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Project description:People with pale skin, red hair, freckles and an inability to tan--the 'red hair/fair skin' phenotype--are at highest risk of developing melanoma, compared to all other pigmentation types. Genetically, this phenotype is frequently the product of inactivating polymorphisms in the melanocortin 1 receptor (MC1R) gene. MC1R encodes a cyclic AMP-stimulating G-protein-coupled receptor that controls pigment production. Minimal receptor activity, as in red hair/fair skin polymorphisms, produces the red/yellow pheomelanin pigment, whereas increasing MC1R activity stimulates the production of black/brown eumelanin. Pheomelanin has weak shielding capacity against ultraviolet radiation relative to eumelanin, and has been shown to amplify ultraviolet-A-induced reactive oxygen species. Several observations, however, complicate the assumption that melanoma risk is completely ultraviolet-radiation-dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and ultraviolet radiation signature mutations are infrequently oncogenic drivers. Although linkage of melanoma risk to ultraviolet radiation exposure is beyond doubt, ultraviolet-radiation-independent events are likely to have a significant role. Here we introduce a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAF(V600E), into mice carrying an inactivating mutation in the Mc1r gene (these mice have a phenotype analogous to red hair/fair skin humans). We observed a high incidence of invasive melanomas without providing additional gene aberrations or ultraviolet radiation exposure. To investigate the mechanism of ultraviolet-radiation-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r(e/e) background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1r(e/e) mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1r(e/e) mouse skin. These data suggest that the pheomelanin pigment pathway produces ultraviolet-radiation-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. Although protection from ultraviolet radiation remains important, additional strategies may be required for optimal melanoma prevention.

Project description:Background: We investigated the effect of PPIA overexpression on downstream gene expression at the cellular level. Methods: The PPIA gene was overexpressed in human umbilical vein endothelial cells. Then, transcriptome sequencing was performed. The differentially expressed genes and genes with alternative splicing were screened. GO and KEGG analyses were performed. Nine differentially expressed genes and 7 genes with alternative splicing were validated by real-time quantitative PCR. Results: After PPIA overexpression, 328 genes were differentially expressed, including 157 up-regulated genes and 171 down-regulated genes. GO enrichment analysis of up-regulated genes found that the enriched GO terms included extracellular region, protein binding and metal ion binding, etc. For down-regulated genes, the enriched GO terms included neuron projection, protein binding, endoplasmic reticulum unfolded protein response, etc. KEGG showed that the up-regulated genes were mainly enriched in gastric acid secretion, AMPK signaling pathway, etc; and, the down-regulated genes were enriched in transcriptional misregulation in cancer, TNF signaling pathway, etc. Real-time quantitative PCR analysis of ATF4 (activating transcription factor 4), PPP1R15A (protein phosphatase 1, regulatory (inhibitor) subunit 15A protein phosphate 1, regulatory (inhibitor) subunit 15A), GADD45B (growth arrest and DNA damage inducible protein 45B), SGK1 (serum/glucocorticoid regulated kinase 1), DDIT3 (Recombinant DNA Damage Inducible Transcript 3), PMAIP1 (Phorbol-12-myristate-13-acetate-induced Protein 1), SULF1 (Sulfatase 1), GDF6 (Growth Differentiation Factor 6), and XBP1 (X-Box Binding Protein 1) obtained consistent results with the sequencing results. On the other hand, multiple genes with alternative splicing were identified and analyzed with KEGG and GO. Real-time quantitative PCR validation showed that the probability of alternative splicing in LHPP, APH1A, BRD1, and ORAI3 was increased. However, the changes of NFX1, SERGEF, and PCBP4 were inconsistent with the sequencing results. Conclusion: The overexpression of PPIA in human umbilical vein endothelial cells causes changes in the expression of downstream genes, and induces alternative splicing in multiple genes. PPIA may be involved in the development of atherosclerosis by regulating the expression of downstream genes and causing endothelial cell dysfunction.

Dataset Information

Deregulation of XPC and CypA by cyclosporin A: an immunosuppression-independent mechanism of skin carcinogenesis.

Publications

Deregulation of XPC and CypA by cyclosporin A: an immunosuppression-independent mechanism of skin carcinogenesis.

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