Identification of key genes and pathways involved in vitiligo development based on integrated analysis.

Vitiligo is a chronic skin condition lack of melanocytes. However, researches on the aetiology and pathogenesis of vitiligo are still under debate. This study aimed to explore the key genes and pathways associated with occurrence and development of vitiligo.Weighted gene coexpression network analysis (WGCNA) was applied to reanalyze the gene expression dataset GSE65127 systematically. Functional enrichments of these modules were carried out at gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set variation analysis (GSVA), and gene set enrichment analysis (GSEA). Then, a map of regulatory network was delineated according to pivot analysis and drug prediction. In addition, hub genes and crucial pathways were validated by an independent dataset GSE75819. The expressions of hub genes in modules were also tested by quantitative real-time polymerase chain reaction (qRT-PCR).Eight coexpressed modules were identified by WGCNA based on 5794 differentially expressed genes of vitiligo. Three modules were found to be significantly correlated with Lesional, Peri-Lesional, and Non-Lesional, respectively. The persistent maladjusted genes included 269 upregulated genes and 82 downregulated genes. The enrichments showed module genes were implicated in immune response, p53 signaling pathway, etc. According to GSEA and GSVA, dysregulated pathways were activated incessantly from Non-Lesional to Peri-Lesional and then to Lesional, 4 of which were verified by an independent dataset GSE75819. Finally, 42 transcription factors and 228 drugs were spotted. Focusing on the persistent maladjusted genes, a map of regulatory network was delineated. Hub genes (CACTIN, DCTN1, GPR143, HADH, MRPL47, NKTR, NUF2) and transcription factors (ITGAV, SYK, PDPK1) were validated by an independent dataset GSE75819. In addition, hub genes (CACTIN, DCTN1, GPR143, MRPL47, NKTR) were also confirmed by qRT-PCR.The present study, at least, might provide an integrated and in-depth insight for exploring the underlying mechanism of vitiligo and predicting potential diagnostic biomarkers and therapeutic targets.

Blocking RhoA/ROCK inhibits the pathogenesis of pemphigus vulgaris by suppressing oxidative stress and apoptosis through TAK1/NOD2-mediated NF-κB pathway.

Oxidative stress and apoptosis play critical roles in pemphigus vulgaris (PV). The main aim of the present study was to investigate the effects of RhoA/ROCK signaling on UVB-induced oxidative damage, and to delineate the molecular mechanisms involved in the UVB-mediated inflammatory and apoptotic response. In HaCaT cells, we observed that blockage of RhoA/ROCK signaling with the inhibitor CT04 or Y27632 greatly inhibited the UVB-mediated increase in intracellular reactive oxygen species (ROS). Additionally, inhibition of RhoA/ROCK signaling reduced UVB-induced apoptosis, as exemplified by a reduction in DNA fragmentation, and also elevated anti-apoptotic Bcl-2 protein, concomitant with reduced levels of pro-apoptotic protein Bax, caspase-3 cleavage and decreased PARP-1 protein. The release of inflammatory mediators TNF-α, IL-1ß, and IL-6 was also attenuated. Mechanically, we observed that blockage of RhoA/ROCK repressed the TAK1/NOD2-mediated NF-κB pathway in HaCaT cells exposed to UVB. Taken together, these data reveal that RhoA/ROCK signaling is one of the regulators contributing to oxidative damage and apoptosis in human keratinocytes, suggesting that RhoA/ROCK signaling has strong potential to be used as a useful therapeutic target in skin diseases including PV.

Secreted frizzled-related protein promotors are hypermethylated in cutaneous squamous carcinoma compared with normal epidermis.

BACKGROUND: The Wnt signaling pathway is abnormally activated in many human cancers. Secreted frizzled-related proteins (SFRPs) function as negative regulators of Wnt signaling and play an important role in carcinogenesis. SFRP promoter hypermethylation has often been identified in human cancers; however, the precise role of SFRPs in cutaneous squamous cell carcinoma (SCC) is unclear. METHODS: The methylation status of the SFRP family was analyzed in an age-and sex-matched case-control study, including 40 cutaneous SCC cases and 40 normal controls, using the MassARRAY EpiTYPER system. RESULTS: The methylation rate of SFRP1, SFRP2, SFRP4, and SFRP5 promoters was significantly higher in cutaneous SCC tissues than in adjacent tissue and normal skin samples. DISCUSSION: Our manuscript mainly discussed the average methylation rate of SFRPs (SFRP1, SFRP2, SFRP4, and SFRP5) promoters are significantly high in tumor tissue samples and the average CpG island methylation rate among different pathological levels of cutaneous SCC between these genes are different. CONCLUSIONS: Our findings suggest that promoter hypermethylation of SFRPs is associated with the development of carcinoma, and could be a useful tumor marker for cutaneous SCC and other types of cancers.

Correlation analysis between activation-induced cytidine deaminase expression and melanoma invasion, metastasis and prognosis / 中华皮肤科杂志

Objective To explore the relationship between activation-induced cytidine deaminase (AID) expression and melanoma invasion, metastasis and prognosis, and to evaluate the clinical significance of AID. Methods An immunohistochemical study was conducted to detect the expression of AID in paraffin-embedded tissue sections from 80 cases of melanoma and 23 cases of pigmented nevus. The relationship between the expression of AID and clinicopathological and biological features of melanoma was analyzed. Results The expression rate of AID was significantly higher in melanoma than in pigmented nevus tissue specimens(53.75%(43/80)vs. 13.04%(3/23), P 0.05). Of 19 melanoma specimens with BRAF mutations, 17 expressed AID, including all the 15 melanoma specimens with the BRAFV600E mutation. Conclusions AID may induce BRAF mutations in melanoma, participate in melanoma invasion and metastasis, and be correlated with melanoma prognosis.

Methylation of SFRP1 gene promoter in cutaneous squamous cell carcinoma tissue / 中华皮肤科杂志

Objective To investigate the relationship between SFRP1 gene and clinicopathologic features of cutaneous squamous cell carcinoma (CSCC), and to explore the possible mechanism of action of SFRP1 in the occurrence and development of CSCC.Methods CSCC and paracarcinomatous tissue specimens were obtained from 40 patients with CSCC, and normal skin tissue specimens from 40 healthy human controls.The EpiTYPER assay was conducted to evaluate the methylation status of SFRP1 gene promoter in all the specimens with a MassARRAY mass spectrometer.Results Totally, the methylation status of 1951 (86.52％, 1951/2255) CpG motifs were evaluated in 17 CpG loci in 2 fragments of the SFRP1 gene promoter.The methylation rate significantly differed in 10 (10/17, 58.82％) CpG loci between the CSCC and paracarcinomatous tissue specimens, and in 5 (5/17, 29.41％) CpG loci between the paracarcinomatous and normal tissue specimens (all P ＜ 0.05).Furthermore, significant differences were observed in the methylation rates of three CpG loci (CpG 1_5, CpG 1_7, CpG 2_8) in the SFRP1 gene promoter between tissue specimens from different pathological grades of CSCC (P ＜ 0.05), and their methylation rates sequentially decreased from grade Ⅲ to grade Ⅱ and Ⅰ.Conclusion The frequency of methylation is high in the SFRP1 gene promoter in patients with CSCC, and the SFRP1 gene may participate in the occurrence and development of CSCC.

Specific substance of Maruyama (SSM) suppresses immune responses in atopic dermatitis-like skin lesions in DS-Nh mice by modulating dendritic cell functions.

BACKGROUND: Specific substance of Maruyama (SSM) is a carcinostatic immunotherapeutic agent extracted from Mycobacterium tuberculosis. The efficacy of SSM induced interleukin(IL)-12 and IFN-γ production, and inhibition of IL-4, resulting in a shift from Th2 to Th1 in vivo. OBJECTIVE: The DS-Nh mice are a model of human atopic dermatitis (AD), which spontaneously develop dermatitis under conventional conditions. In this study, to determine whether SSM can prevent the development of skin lesions in a murine model of AD. METHODS: DS-Nh mice were injected with SSM 5 days per week for 11 weeks. Pharmacological, histological and serological studies were performed to investigate the therapeutic effect of SSM for DS-Nh mice. Analysis of cytokines responses to SSM using quantitative RT-PCR and flow cytometry were also performed to evaluate their therapeutic mechanisms in these AD model mice. RESULTS: Clinically, erythema, erosions, excoriation, and edema were observed in DS-Nh mice at 16 weeks of age, which advanced with age. Histologically, the relative number of mast cells increased in DS-Nh mice. SSM treatment alleviated the clinical and histological findings in accord with reduced serum IgE level, and increased IgG2a level. TSLP expression was not induced, but IL-1ß, IL-12, IL-17A, and IFN-γ were induced in SSM-treated DS-Nh mice. Overall, SSM treatments increased the number of activated DCs in lesions. SSM induced CD80, CD86, and MHC class II expression on bone marrow-derived DCs. CONCLUSIONS: SSM enhanced IL-12 production, but suppressed TSLP expression, resulting in a shift from Th2 to Th1 responses. This shift suppressed AD-like skin lesions in a similar fashion as the BCG vaccine. Therefore, SSM may be a useful adjuvant for suppressing skin lesions in AD models.