GWAS of Chronic Spontaneous Urticaria Reveals Genetic Overlap with Autoimmune Diseases, Not Atopic Diseases.

Although chronic spontaneous urticaria (CSU) is a common disease, GWASs of CSU are lacking. We aimed to identify susceptibility SNPs by performing a GWAS in Chinese Han adults with CSU. The discovery cohort included 430 CSU cases and 482 healthy controls. The GWAS findings were validated in 800 CSU cases and 900 healthy controls. Genetic, functional enrichment, and bioinformatic analyses of genome-wide significant SNPs were performed to assess the association between CSU and autoimmunity or atopy. Five genome-wide significant SNPs were identified: rs434124/LILRA3, rs61986182/IGHG1/2, rs73075571/TDGF1, rs9378141/HLA-G, and rs3789612/PTPN22. The first four SNPs were in linkage disequilibrium with autoimmune-related diseases‒associated SNPs and were cis-expression quantitative trait loci in immune cells. The five SNPs-annotated genes were significantly enriched in immune processes. Higher polygenic risk scores and allele frequencies of rs3789612∗T, rs9378141∗C, and rs73075571∗G were significantly associated with autoimmune-related CSU phenotypes, including positive antithyroglobulin IgG, positive anti-FcεRIα IgG, total IgE <40 IU/ml, and positive antithyroid peroxidase IgG but not with atopic or allergic sensitized CSU phenotypes. This GWAS of CSU identifies five risk loci and reveals that CSU shares genetic overlap with autoimmune diseases and that genetic factors predisposing to CSU mainly manifest through associations with autoimmune traits.

A comprehensive evaluation of skin aging-related circular RNA expression profiles.

BACKGROUND: Circular RNAs (circRNAs) have been shown to play important regulatory roles in a range of both pathological and physiological contexts, but their functions in the context of skin aging remain to be clarified. In the present study, we therefore, profiled circRNA expression profiles in four pairs of aged and non-aged skin samples to identify identifying differentially expressed circRNAs that may offer clinical value as biomarkers of the skin aging process. METHODS: We utilized an RNA-seq to profile the levels of circRNAs in eyelid tissue samples, with qRT-PCR being used to confirm these RNA-seq results, and with bioinformatics approaches being used to predict downstream target miRNAs for differentially expressed circRNAs. RESULTS: In total, we identified 571 circRNAs with 348 and 223 circRNAs being up and downregulated that were differentially expressed in aged skin samples compared to young skin samples. The top 10 upregulated circRNAs in aged skin sample were hsa_circ_0123543, hsa_circ_0057742, hsa_circ_0088179, hsa_circ_0132428, hsa_circ_0094423, hsa_circ_0008166, hsa_circ_0138184, hsa_circ_0135743, hsa_circ_0114119, and hsa_circ_0131421. The top 10 reduced circRNAs were hsa_circ_0101479, hsa_circ_0003650, hsa_circ_0004249, hsa_circ_0030345, hsa_circ_0047367, hsa_circ_0055629, hsa_circ_0062955, hsa_circ_0005305, hsa_circ_0001627, and hsa_circ_0008531. Functional enrichment analyses revealed the potential functionality of these differentially expressed circRNAs. The top 3 enriched gene ontology (GO) terms of the host genes of differentially expressed circRNAs are regulation of GTPase activity, positive regulation of GTPase activity and autophagy. The top 3 enriched KEGG pathway ID are Lysine degradation, Fatty acid degradation and Inositol phosphate metabolism. The top 3 enriched reactome pathway ID are RAB GEFs exchange GTP for GDP on RABs, Regulation of TP53 Degradation and Regulation of TP53 Expression and Degradation. Six circRNAs were selected for qRT-PCR verification, of which 5 verification results were consistent with the sequencing results. Moreover, targeted miRNAs, such as hsa-miR-588, hsa-miR-612, hsa-miR-4487, hsa-miR-149-5p, hsa-miR-494-5p were predicted for circRna-miRna interaction networks. CONCLUSION: Overall, these results offer new insights into circRNA expression profiles, potentially highlighting future avenues for research regarding the roles of these circRNAs in the context of skin aging.

The Current State of Research Regarding the Role of Non-Coding RNAs in Cutaneous Squamous Cell Carcinoma.

Skin cancers, including those of both both melanoma and non-melanoma subtypes, remain among the most common forms of human cancer. Non-melanoma skin cancers are typically further differentiated into the basal cell carcinoma and cutaneous squamous cell carcinoma (cSCC) categories. Current approaches to diagnosing and treating cSCC remain unsatisfactory, and the prognosis for patients with this disease is relatively poor. Recent advances in high-throughput sequencing have led to an increasingly robust understanding of the diversity of non-coding RNAs (ncRNAs) expressed in both physiological and pathological contexts. These ncRNAs include microRNAs, long ncRNAs, and circular RNAs, all of which have been found to play key functional roles and/or to have value as diagnostic biomarkers or therapeutic targets in a range of different disease contexts. The number of ncRNAs associated with cSCC continues to rise, and as such, there is clear value in comprehensively reviewing the functional roles of these molecules in this form of cancer in order to highlight future avenues for research and clinical development.

RNA-Seq Profiling of Circular RNAs and the Oncogenic Role of circPVT1 in Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is associated with a poor 5-year survival rate. circRNAs have an important role in a number of physiological and pathological processes. However, the relationship between circRNAs and cutaneous squamous cell carcinoma (CSCC) is unclear. PURPOSE: The aim of the present study was to investigate the expression of circRNAs in cutaneous squamous cell carcinoma (CSCC) and its effect on CSCC proliferation and metastasis. METHODS: We used high-throughput sequencing (RNA-seq) to identify circRNAs that were differentially in CSCC tissue and their paracarcinoma tissue. Quantitative real-time PCR results confirm deep-sequencing findings in CSCC tissue and cell lines. CCK-8 assay and flow cytometry were used to detect the effect of circPVT1 on the proliferation and migration of CSCC cells. RESULTS: We identified 449 circRNAs that were differentially expressed between CSCC and normal adjacent tissue samples. circPVT1 (hsa_circ_0001821) was further researched to confirm its oncogene role in CSCC. CONCLUSION: Differentially expressed circular RNA plays an important role in the development of CSCC, and circPVT1 may be an important target for the treatment of CSCC.

Identification of a five-miRNA signature predicting survival in cutaneous melanoma cancer patients.

BACKGROUND: Cutaneous melanoma (CM) is the deadliest form of skin cancer. Numerous studies have revealed that microRNAs (miRNAs) are expressed abnormally in melanoma tissues. Our work aimed to assess multiple miRNAs using bioinformatic analysis in order to predict the prognoses of cutaneous melanoma patients. METHODS: The microarray dataset GSE35579 was downloaded from the Gene Expression Omnibus (GEO) database to detect the differential expression of miRNAs (DEMs), including 41 melanoma (primary and metastatic) tissues and 11 benign nevi. Clinical information and miRNA sequencing data of cutaneous melanoma tissues were downloaded from the Cancer Genome Atlas database (TCGA) to assess the prognostic values of DEMs. Additionally, the target genes of DEMs were anticipated using miRanda, miRmap, TargetScan, and PicTar. Finally, functional analysis was performed using selected target genes on the Annotation, Visualization and Integrated Discovery (DAVID) website. RESULTS: After performing bioinformatic analysis, a total of 185 DEMs were identified: 80 upregulated miRNAs and 105 downregulated miRNAs. A five-miRNA (miR-25, miR-204, miR-211, miR-510, miR-513c) signature was discovered to be a potential significant prognostic biomarker of cutaneous melanoma when using the Kaplan-Meier survival method (P = 0.001). Univariate and multivariate Cox regression analyses showed that the five-miRNA signature could be an independent prognostic marker (HR = 0.605, P = 0.006) in cutaneous melanoma patients. Biological pathway analysis indicated that the target genes may be involved in PI3K-Akt pathways, ubiquitin-mediated proteolysis, and focal adhesion. CONCLUSION: The identified five-miRNA signature may serve as a prognostic biomarker, or as a potential therapeutic target, in cutaneous melanoma patients.

Trichostatin A­induced miR­30a­5p regulates apoptosis and proliferation of keloid fibroblasts via targeting BCL2.

Keloids are benign fibrous overgrowths that occur as a result of abnormal wound healing following cutaneous injury. MicroRNAs (miRNAs/miRs) are short non­coding RNAs that serve critical roles in numerous important biological processes, such as cell proliferation, differentiation and apoptosis. However, their role in keloid development remains largely unknown. In the present study, the role of miR­30a­5p, a miRNA regulated by Trichostatin A (TSA), in apoptosis within cultured keloid fibroblasts was investigated. An MTT assay was used to detect the proliferation of cultured keloid fibroblasts treated with TSA. Cell apoptosis and cell cycle phases were analyzed using flow cytometry. In addition, an miRNA microarray was performed to compare expression profiles between cultured keloid fibroblasts treated with or without 1,000 nM TSA. Reverse transcription­quantitative polymerase chain reaction analysis was conducted to estimate miRNA expression levels. The direct target of miR­30a­5p was identified using a dual­luciferase reporter assay. Western blotting was employed to assess protein expression levels in keloid fibroblasts. The results demonstrated that TSA inhibited the proliferation of keloid fibroblasts in a time­ and dose­dependent manner. The miRNA microarray revealed alterations in the expression of numerous miRNA sequences in response to TSA when compared with controls. Notably, the expression of miR­30a­5p was downregulated in keloid tissues. In addition, overexpression of miR­30a­5p induced apoptosis by targeting B­cell lymphoma 2, which was similar to that observed in response to TSA. These results provide important information regarding a novel miR­30a­5p­mediated signaling pathway induced by TSA treatment, and suggest a potential use for TSA and miR­30a­5p as effective therapeutic strategies for keloids.

Author Correction: Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.

This corrects the article DOI: 10.1038/ncomms7793.

Prevalence and risk of metabolic syndrome in patients with systemic lupus erythematosus: A meta-analysis.

PURPOSE: To conduct a systematic review and meta-analysis assessing the prevalence of metabolic syndrome (MetS) in patients with systemic lupus erythematosus (SLE) and the association between SLE and MetS. METHOD: A database search of PubMed, the Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Weipu database and Wanfang database updated until March 2017 was conducted. The pooled prevalence, the odds ratio (OR) and 95% confidence intervals (CI) were calculated. Publication bias was assessed with Egger's test method. RESULTS: In the study of the prevalence of MetS in patients with SLE, 47 studies containing 8367 subjects were included. These studies were published from 2006 to 2016. The pooled prevalence of MetS in patients with SLE was 0.26 (95% CI: 0.23-0.29). In the study of the relationship between SLE and MetS, 24 studies involving 2744 cases and 3028 controls were included. Comparing to control, the SLE patients had high risk of MetS (OR = 1.88, 95% CI: 1.54-2.30, P = 0.000). CONCLUSION: The systematic review and meta-analysis demonstrated the prevalence of MetS in patients with SLE was 26% and the patients with SLE were more prone to having MetS than the control population. The analysis was a basic summary of all relevant researches and provided valuable evidence for prevention and treatment.

Adiponectin Is Involved in Connective Tissue Growth Factor-Induced Proliferation, Migration and Overproduction of the Extracellular Matrix in Keloid Fibroblasts.

Adiponectin, an adipocyte-derived hormone, exerts pleiotropic biological effects on metabolism, inflammation, vascular homeostasis, apoptosis and immunity. Recently, adiponectin has been suggested to attenuate the progression of human dermal fibrosis. Connective tissue growth factor (CTGF) is induced in keloids and is thought to be participated in the formation of keloid fibrosis. However, the roles played by adiponectin in keloids remain unclear. In this study, we explored the effects of adiponectin on CTGF-induced cell proliferation, migration and the deposition of extracellular matrix (ECM) and their associated intracellular signalling pathways in keloid fibroblasts (KFs). We also explored possible mechanisms of keloid pathogenesis. Primary fibroblast cultures were established from foreskin biopsies and skin biopsies from patients with keloids. The expression of adiponectin and adiponectin receptors (adipoRs) was evaluated by reverse transcription-PCR (RT-PCR), quantitative real-time RT-PCR, immunofluorescence staining, and immunohistochemical analysis. Next, KFs and normal dermal fibroblasts (NFs) were treated with CTGF in the presence or absence of adiponectin. A cell counting kit-8 (CCK-8) and the Transwell assay were used to examine cell proliferation and migration. The level of the collagen I, fibronectin (FN) and α-smooth muscle actin (α-SMA) mRNAs and proteins were determined by quantitative real-time RT-PCR and western blotting. The effects of RNA interference (RNAi) targeting the adipoR genes were detected. Phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase-protein kinase (PI3K-Akt) were examined by western blotting to further investigate the signalling pathways. Furthermore, inhibitors of signal transduction pathways were investigated. The expression levels of adiponectin and adipoRs were significantly decreased in keloids compared with those in normal skin tissue. Adiponectin suppressed the CTGF-induced KFs, but not NFs, proliferation, migration and ECM production. Moreover, adiponectin inhibited the phosphorylation of AMPK, p38 and extracellular-regulated kinase (ERK), but not that of Jun N-terminal kinase (JNK) or Akt, in CTGF-treated KFs. The activity of adiponectin-mediated signalling pathways was attenuated by small interfering RNAs (siRNAs) targeting adipoR1 (but not siRNAs targeting adipoR2, T-cadherin or calreticulin), AMPK (Compound C), p38 (SB203580) inhibitors, and mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059). Based on our results, adiponectin suppresses CTGF-induced KFs proliferation, migration and ECM overproduction. One of the underlying mechanisms is the activation of the adipoR1, AMPK, p38, and ERK signalling pathways. Therefore, adiponectin may play an important role in the progression of keloids, suggesting a potential novel target for keloid treatment.

Maspin suppresses growth, proliferation and invasion in cutaneous squamous cell carcinoma cells.

Cutaneous squamous cell carcinoma (cSCC) is a common malignant tumor. Mammary serine protease inhibitor (Maspin), a member of serpin family, has been reported as a tumor suppressor in various carcinomas. In this study, we detected the expression level of Maspin in cSCC tissues by real-time PCR and western blotting, and found that Maspin was downregulated in the cSCC tissues compared with the adjacent normal tissues. Moreover, Maspin was stably overexpressed in A431 cells, and CCK-8 assay, colony formation assay, Transwell assay, Hoechst staining and western blotting were carried out to detect the growth, proliferation, invasion, cell cycle and apoptosis of A431 cells. The results revealed that overexpression of Maspin inhibited growth, proliferation, invasion and cell cycle G1/S/G2 transition and enhanced apoptosis of A431 cells. The pro-apoptotic protein cleaved caspase-3, poly(ADP-ribose) polymerase (PARP) and Bax increased, and the anti-apoptotic protein Bcl-2 decreased after Maspin overexpression. Therefore, we demonstrated that Maspin suppressed growth, proliferation and invasion by delaying cell cycle transition and promoting apoptosis in cSCC cells, which may provide new insights for the clinical diagnosis and therapy of cSCC.

Synthesis and characterization of a new retinoic acid ECPIRM as potential chemotherapeutic agent for human cutaneous squamous carcinoma.

Cutaneous squamous cell carcinoma (CSCC) is one of the most common cancers worldwide, requiring effective therapeutic interventions. Retinoids are important chemopreventive and therapeutic agents for a variety of human cancers including CSCC. In this study we synthesized a novel retinoic derivative N-(4-ethoxycarbonylphenyl) isoretinamide (ECPIRM) and evaluated its biological activities and possible mechanisms in human cutaneous squamous cell lines. ECPIRM had better inhibitory effect on the proliferation of squamous carcinoma cells SCL-1 and colo-16, compared with All-trans retinoic acid and 13-cis retinoic acid. ECPIRM had less toxicity to normal keratinocyte cell line HaCaT. Mechanistically, ECPIRM induced G1 cell cycle arrest in SCL-1 cells, via the downregulation of CDK2, CDK4, cycling D1 and cyclin E expression and upregulation of p21. In addition, these effects were at least partially due to the inhibition of JNK/ ERK-AP-1 signaling pathway by ECPIRM. Importantly, these effects of ECPIRM are independent of the classical retinoid receptor pathway, suggesting that the novel compound will have less side-effects in chemotherapy. These findings demonstrate that ECPIRM is a potential inhibitor of MPAK-AP-1 pathway, and is a potential therapeutic agent against CSCC.

Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.

Genome-wide association studies (GWASs) have reproducibly associated ∼40 susceptibility loci with psoriasis. However, the missing heritability is evident and the contributions of coding variants have not yet been systematically evaluated. Here, we present a large-scale whole-exome array analysis for psoriasis consisting of 42,760 individuals. We discover 16 SNPs within 15 new genes/loci associated with psoriasis, including C1orf141, ZNF683, TMC6, AIM2, IL1RL1, CASR, SON, ZFYVE16, MTHFR, CCDC129, ZNF143, AP5B1, SYNE2, IFNGR2 and 3q26.2-q27 (P<5.00 × 10(-08)). In addition, we also replicate four known susceptibility loci TNIP1, NFKBIA, IL12B and LCE3D-LCE3E. These susceptibility variants identified in the current study collectively account for 1.9% of the psoriasis heritability. The variant within AIM2 is predicted to impact protein structure. Our findings increase the number of genetic risk factors for psoriasis and highlight new and plausible biological pathways in psoriasis.

Higher 17α-hydroxyprogesterone levels aggravated the severity of male adolescent acne in Northeast China.

BACKGROUND: The relationship between serum hormone levels and adolescent acne is not fully clarified. OBJECTIVE: To determine the relationship between levels of androstenedione, dehydroepiandrosterone sulfate (DHEA-S), testosterone, estradiol and 17α-hydroxyprogesterone (17-OHP) with adolescent acne in Northeast China. METHODS: A transversal study included 242 acne cases and 188 controls. All data were analyzed using SPSS version 17.0. RESULTS: Androstenedione and testosterone levels were significantly higher (p < 0.0001) in the cases than in the control group. In males, the difference in 17-OHP levels was statistically significant (p < 0.0001), as well as between mild and severe acne cases (p = 0.002). The estradiol level was significantly different (p < 0.0001) between cases and controls in females. CONCLUSION: Higher androstenedione and testosterone levels are significant risk factors in the occurrence of adolescent acne. A higher 17-OHP level aggravates the severity of male adolescent acne, while a higher estradiol level protects females against the onset of adolescent acne.

A functional SNP in the MDM2 promoter mediates E2F1 affinity to modulate cyclin D1 expression in tumor cell proliferation.

BACKGROUND: The MDM2 oncogene, a negative regulator of p53, has a functional polymorphism in the promoter region (SNP309) that is associated with multiple kinds of cancers including non-melanoma skin cancer. SNP309 has been shown to associate with accelerated tumor formation by increasing the affinity of the transcriptional activator Sp1. It remains unknown whether there are other factors involved in the regulation of MDM2 transcription through a trans-regulatory mechanism. METHODS: In this study, SNP309 was verified to be associated with overexpression of MDM2 in tumor cells. Bioinformatics predicts that the T to G substitution at SNP309 generates a stronger E2F1 binding site, which was confirmed by ChIP and luciferase assays. RESULTS: E2F1 knockdown downregulates the expression of MDM2, which confirms that E2F1 is a functional upstream regulator. Furthermore, tumor cells with the GG genotype exhibited a higher proliferation rate than TT, correlating with cyclin D1 expression. E2F1 depletion significantly inhibits the proliferation capacity and downregulates cyclin D1 expression, especially in GG genotype skin fibroblasts. Notably, E2F1 siRNA effects could be rescued by cyclin D1 overexpression. CONCLUSION: Taken together, a novel modulator E2F1 was identified as regulating MDM2 expression dependent on SNP309 and further mediates cyclin D1 expression and tumor cell proliferation. E2F1 might act as an important factor for SNP309 serving as a rate-limiting event in carcinogenesis.

Treatment and mortality rate of bullous pemphigoid in China: a hospital-based study.

Bullous pemphigoid (BP) has been reported to be associated with significant morbidities and a considerable mortality rate. We retrospectively studied 94 patients with BP in a Chinese tertiary medical center between 2005 and 2010 to evaluate the treatment of BP and prognostic factors for the mortality of BP. Cerebrovascular diseases (42.55%) and hypertension (39.36%) were the most common pre-existing conditions. Cardiopathy, diabetes and psoriasis pre-existed in 24.47%, 22.34% and 5.32%, respectively. Eighty of all 94 patients were treated by systemic corticosteroid at prednisone 0.3 mg/kg to 1.5 mg/kg daily. Patients were followed up for a minimum of 1 year or until the time of death. The mean duration of follow-up was 32 months. Kaplan-Meier analysis showed a 1-year survival probability of 76.6% (standard error 4.4%), with a 95% confidence interval (68.04%, 85.16%). Multivariate analysis revealed that increased age, bedridden condition, presence of cerebrovascular diseases at diagnosis, pre-existing cardiopathy and low serum albumin level were associated with the elevated 1-year mortality rate of BP.

Baicalein inhibits DMBA/TPA-induced skin tumorigenesis in mice by modulating proliferation, apoptosis, and inflammation.

Baicalein, one of the four major flavanoids extracted from the root of Scutellaria baicalensis, has been shown to exert chemopreventive effect against several cancers, including skin cancer. However, the precise mechanisms remain to be elucidated. In the present study, we investigated the chemopreventive activity of baicalein against 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated skin tumorigenesis in C57BL/6 mice. We found that topical treatment with baicalein resulted in a significant inhibitory effect on DMBA/TPA-mediated tumor promotion. Furthermore, we observed that baicalein suppressed cell proliferation and promoted apoptosis in DMBA/TPA-mediated group. Additionally, pretreatment with baicalein inhibited the production of inflammatory cells in DMBA/TPA-induced skin/tumors. Further experiments showed that baicalein reduced TPA-induced skin hyperplasia as well as infiltration of polymorphonuclear leukocytes in the dermis. In conclusion, our data suggest that baicalein inhibits DMBA/TPA-induced skin tumorigenesis by suppressing proliferation and inflammation and promoting apoptosis.

Blocking glutamate-mediated signalling inhibits human melanoma growth and migration.

Glutamate is an excitatory neurotransmitter that has been shown to regulate the proliferation, migration and survival of neuronal progenitors in the central nervous system through its action on metabotropic and ionotropic glutamate receptors (GluRs). Antagonists of ionotropic GluRs have been shown to cause a rapid and reversible change in melanocyte dendritic morphology, which is associated with the disorganization of actin and tubulin microfilaments in the cytoskeleton. Intracellular expression of microtubule-associated protein (MAP) 2a affects the assembly, stabilization and bundling of microtubules in melanoma cells; stimulates the development of dendrites; and suppresses melanoma cell migration and invasion. In this study, we investigated the relationship between glutamate-mediated signalling and microtubules, cell dendritic morphology and melanoma cell motility. We found that metabotropic GluR1 and N-methyl-d-aspartate receptor antagonists increased dendritic branching and inhibited the motility, migration and proliferation of melanoma cells. We also demonstrated that the invasion and motility of melanoma cells are significantly inhibited by the combination of increased expression of MAP2a and either metabotropic GluR1 or N-methyl-d-aspartate receptor antagonists. Moreover, the blockade of glutamate receptors inhibited melanoma growth in vivo. Collectively, these results demonstrate the importance of glutamate signalling in human melanoma and suggest that the blockade of glutamate receptors is a promising novel therapy for treating melanoma.