RESUMEN
BACKGROUND: SPRR1B, a member of the small proline-rich protein family, is implicated in various epithelial cancers as a potential oncogene linked to tumour growth and poor survival outcomes. However, its role in urothelial bladder carcinoma (UBC) remains to be fully elucidated. METHODS: Transcriptional profiling data from The Cancer Genome Atlas grouped UBC samples in accordance with SPRR1B expression. Bioinformatic analysis was conducted to evaluate whether SPRR1B is a prognostic factor and a survival factor in UBC. Gene set enrichment analysis (GSEA) was performed to study immune cells and pathways. Reverse transcription quantitative real-time polymerase chain reaction detected gene expression. Immunohistochemistry assessed protein expression. Spearman correlation test analysed the correlation between SPRR1B and the protein p53. RESULTS: The bioinformatics results indicated that the expression level of SPRR1B in UBC tissues was significantly increased compared with that in normal bladder tissues, correlating with clinical characteristics. A high expression predicted poor prognosis and survival. Univariate Cox statistics showed that a high expression level of SPRR1B was correlated with UBC patients having poor overall survival (OS) (p < 0.05). In addition, on the basis of the multivariate Cox analysis, SPRR1B expression was independently correlated with OS (p = 0.005). GSEA analysis revealed enrichment in the p53, apoptosis, and cell cycle signalling pathways, and an association with B cells, lymphocytes, and natural killer cells. In addition, SPRR1B was found to be associated with immune infiltration based on the analysis of immune cell infiltration. Performing corresponding verification on a small number of tissues collected from bladder cancer patients revealed that the expression of this protein was negatively correlated with the expression of p53. CONCLUSIONS: SPRR1B overexpression predicts poor UBC outcomes, suggesting its role as a prognostic marker and therapeutic target. Further research is necessary to elucidate its role in UBC progression.
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Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/mortalidad , Pronóstico , Masculino , Femenino , Anciano , Proteínas Ricas en Prolina del Estrato Córneo/genética , Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Persona de Mediana Edad , Tasa de Supervivencia , Regulación Neoplásica de la Expresión GénicaRESUMEN
Cornulin (CRNN) and repetin (RPTN) belong to the fused-type S100 protein family. Although these proteins have been reported to be expressed in the granular layer of the epidermis and have been suggested to be associated with barrier formation in the epidermis, their exact function remains unclear. This study examined the effects of ultraviolet B (UVB) irradiation on CRNN and RPTN expression in human skin xenotransplantation. The CRNN expression increased in the granular layer of UVB-irradiated skin 2 days after UVB irradiation compared to that in sham-irradiated skin. Interestingly, CRNN signals were observed not only in the cytoplasm, but also in the peripheral regions of granular keratinocytes. In contrast, RPTN was rarely expressed in sham-irradiated skin; however, RPTN signals were markedly increased in the granular layer of the UVB-irradiated skin. In addition, activation of ERK1/2 and STAT3 was observed in UVB-irradiated skin. Accordingly, the present study demonstrated that CRNN and RPTN are novel proteins whose expression can be increased by UVB irradiation. The activation of ERK1/2 and STAT3 may be associated with the regeneration of a UVB-damaged epidermis, and CRNN and RPTN may be induced to repair any dysfunction in the epidermal barrier during this regeneration process.
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Factor de Transcripción STAT3 , Rayos Ultravioleta , Humanos , Factor de Transcripción STAT3/metabolismo , Trasplante Heterólogo , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Animales , Piel/metabolismo , Piel/efectos de la radiación , Epidermis/metabolismo , Epidermis/efectos de la radiación , Trasplante de Piel , Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Proteínas Ricas en Prolina del Estrato Córneo/genética , Xenoinjertos , Proteínas S100/metabolismo , Proteínas S100/genética , RatonesRESUMEN
In sexual assault cases, it is crucial to discriminate between peripheral blood and menstrual blood to provide evidence for vaginal intercourse with traumatic injury. In this study, the menstrual blood mRNA markers progestagen-associated endometrial protein (PAEP), matrix metallopeptidase 7 (MMP7), and left-right determination factor 2 (LEFTY2) were evaluated by quantitative RT-PCR (RT-qPCR) for the discrimination of menstrual blood from peripheral blood and vaginal fluid. As a result, all markers with cutoff delta cycle quantification (ΔCq) values were specifically determined in menstrual blood among forensically relevant body fluids. Even though the changes in the expression levels of each marker differed during the menstrual cycle, all markers were determined to be positive in most of the randomly collected menstrual blood samples that were analyzed. Additionally, the markers with proposed cutoff ΔCq values could discriminate between menstrual blood and peripheral blood-mixed vaginal fluid samples. The determination of positive markers was less affected by storage temperature under dry conditions than under wet conditions, while PAEP was detectable in samples stored below room temperature under wet conditions. The detectability of PAEP was considered to be the result of its higher expression level compared with MMP7 and LEFTY2. In conclusion, menstrual blood markers for the RT-qPCR procedure evaluated in this study were highly specific for menstrual blood. The proposed procedure could be useful for discriminating between menstruation and traumatic bleeding in the female genital tract. In particular, PAEP is expected to be applicable to forensic casework samples because of its high specificity and robustness.
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Metaloproteinasa 7 de la Matriz , Menstruación , ARN Mensajero , Reacción en Cadena en Tiempo Real de la Polimerasa , Vagina , Humanos , Femenino , Vagina/lesiones , Metaloproteinasa 7 de la Matriz/genética , Endometrio/metabolismo , Adulto , Biomarcadores , Adulto Joven , Delitos Sexuales , Proteínas Ricas en Prolina del Estrato Córneo/genética , Manejo de EspecímenesRESUMEN
Late cornified envelope (LCE) proteins are small cationic epidermal proteins with antimicrobial properties, and the combined deletion of LCE3B and LCE3C genes is a risk factor for psoriasis that affects skin microbiome composition. In a yeast two-hybrid screen, we identified CYSRT1 as an interacting partner of members of all LCE groups except LCE6. These interactions were confirmed in a mammalian cell system by coimmunoprecipitation. CYSRT1 is a protein of unknown function that is specifically expressed in cutaneous and oral epithelia and spatially colocalizes with LCE proteins in the upper layers of the suprabasal epidermis. Constitutive CYSRT1 expression is present in fully differentiated epidermis and can be further induced in vivo by disruption of the skin barrier upon stratum corneum removal. Transcriptional regulation correlates to keratinocyte terminal differentiation but not to skin bacteria exposure. Similar to LCEs, CYSRT1 was found to have antibacterial activity against Pseudomonas aeruginosa. Comparative gene sequence analysis and protein amino acid alignment indicate that CYSRT1 is highly conserved among vertebrates and has putative antimicrobial activity. To summarize, we identified CYSRT1 in the outer skin layer, where it colocalizes with LCE proteins and contributes to the constitutive epidermal antimicrobial host defense repertoire.
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Antiinfecciosos , Psoriasis , Antiinfecciosos/metabolismo , Proteínas Ricas en Prolina del Estrato Córneo/genética , Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Epidermis/metabolismo , Queratinocitos/metabolismo , Proteínas/metabolismo , Psoriasis/genética , Psoriasis/metabolismo , Piel/metabolismo , HumanosRESUMEN
Particulate matter (PM2.5) is an environmental pollutant causing skin inflammatory diseases via epidermal barrier damage. However, the mechanism and related gene expression induced by PM2.5 remains unclear. Our aim was to determine the effect of PM2.5 on human skin tissue ex vivo, and elucidate the mechanism of T helper 17 cell-related inflammatory cytokine and skin barrier function. We verified the expression levels of gene in PM2.5-treated human skin tissue using Quantseq (3' mRNA-Seq), and Gene Ontology (GO) terms and protein-protein interaction (PPI) networks were performed. The PM2.5 treatment significantly enhanced the expression of Th 1, 2, 17 and 22 cell-related genes (cut-off value: â1.2 â > fold change and p < 0.05). Most of all, Th17 cell-related genes are upregulated and those genes are associated with skin epidermal barrier function and Aryl hydrocarbon receptor (AhR), a xenobiotic receptor, pathway. In human keratinocyte cell lines, AhR-regulated genes (e.g. AhRR, CYP1A1, IL6 and IL36G), Th17 cell-related genes (e.g. IL17C) and epidermal barrier-related genes (e.g. SPRR2A and KRT71) are significantly increased after PM2.5. In the protein level, the secretion of IL-6 and IL-36G was increased in human skin tissue following PM2.5 treatment, and the expression of SPRR2A and KRT71 was significantly increased. PM2.5 exposure could ruin the skin epidermal barrier function via AhR- and Th17 cell-related inflammatory pathway.
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Material Particulado , Receptores de Hidrocarburo de Aril , Humanos , Proteínas Ricas en Prolina del Estrato Córneo/genética , Perfilación de la Expresión Génica , Inflamación/genética , Inflamación/metabolismo , Material Particulado/toxicidad , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Células Th17/metabolismo , Piel/inmunologíaRESUMEN
Background: Oral lichen planus (OLP) is a chronic autoimmune oral mucosal disease that seriously affects the life quality of the patients. But till now, the exact etiology and pathogenesis of OLP remain unclear. Our study is aimed at finding the key molecules and pathways involved in the pathogenesis mechanisms of OLP, providing more effective therapeutic strategies for OLP. Methods: Data from GSE52130 were downloaded from GEO datasets for analysis. Then, we carried out enrichment analysis of the differentially expressed genes (DEGs) using Gene Ontology (GO) and KEGG pathway analyses. Next, the CIBERSORT algorithm was used to assess immune cell infiltration in OLP patients. Furthermore, we also constructed a protein-protein interaction network using STRING and Cytoscape and simultaneously sought potential transcription factors plug-in including MCODE CytoHubba and iRegulon. In addition, ROC analysis was employed to assess the diagnostic performance of these hub genes. Lastly, we identified 6 promising novel drugs to treat OLP through Connectivity Map. Results: We illustrated that 255 DEGs were mainly enriched in the focal adhesion pathway and metabolism pathways. Besides, Cibersort analysis showed that M1 macrophages, T follicular helper cells, and T regulatory cells are more infiltrated in OLP samples. In addition, ROC analysis demonstrated that these hub genes owned higher diagnostic value in OLP, in which SPRR1B had the highest diagnostic value. And we also predicted that SOX7 was the most relevant transcription factor of those hub genes. Lastly, through the CMap database, we identified 6 small molecules as possible treatment drugs of OLP. Conclusion: Our research identified that SPRR1B could be used as potential biomarkers for the early diagnosis of OLP. In addition, as a chronic autoimmune oral mucosal disease, OLP has different infiltration types of immune cells. Furthermore, 6 small molecules were proposed as promising novel treatment drugs for OLP patients. Therefore, our research may provide new impetus for the development of effective OLP biological treatment options.
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Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Liquen Plano Oral/diagnóstico , Liquen Plano Oral/inmunología , Macrófagos/inmunología , Linfocitos T/inmunología , Biomarcadores/metabolismo , Proteínas Ricas en Prolina del Estrato Córneo/genética , Bases de Datos Genéticas , Diagnóstico Precoz , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Liquen Plano Oral/genética , Liquen Plano Oral/metabolismo , Mapas de Interacción de Proteínas , Curva ROCRESUMEN
Late cornified envelope proteins are predominantly expressed in the skin and other cornified epithelia. On the basis of sequence similarity, this 18-member homologous gene family has been subdivided into six groups. The LCE3 proteins have been the focus of dermatological research because the combined deletion of LCE3B and LCE3C genes (LCE3B/C-del) is a risk factor for psoriasis. We previously reported that LCE3B/C-del increases the expression of the LCE3A gene and that LCE3 proteins exert antibacterial activity. In this study, we analyzed the antimicrobial properties of other family members and the role of LCE3B/C-del in the modulation of microbiota composition of the skin and oral cavity. Differences in killing efficiency and specificity between the late cornified envelope proteins and their target microbes were found, and the amino acid content rather than the order of the well-conserved central domain of the LCE3A protein was found responsible for its antibacterial activity. In vivo, LCE3B/C-del correlated with a higher beta-diversity in the skin and oral microbiota. From these results, we conclude that all late cornified envelope proteins possess antimicrobial activity. Tissue-specific and genotype-dependent antimicrobial protein profiles impact skin and oral microbiota composition, which could direct toward LCE3B/C-delâassociated dysbiosis and a possible role for microbiota in the pathophysiology of psoriasis.
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Proteínas Ricas en Prolina del Estrato Córneo , Microbiota , Psoriasis , Proteínas Ricas en Prolina del Estrato Córneo/genética , Eliminación de Gen , Predisposición Genética a la Enfermedad , Humanos , Microbiota/genética , Polimorfismo de Nucleótido Simple , Psoriasis/genética , Factores de RiesgoRESUMEN
BACKGROUND Psoriasis is a chronic, immune-mediated and hyperproliferative skin disease with both genetic and environmental components. Copy number variations (CNV) of IL22 and LCE3C-LCE3B deletion have been confirmed to be predisposed to psoriasis vulgaris (PsV) in several ethnic groups. However, it remains to be clarified whether CNVs of IL22 and LCE3C are associated with different subtypes of psoriasis (psoriatic arthritis, PsA; erythrodermic psoriasis, EP; and generalized pustular psoriasis, GPP). MATERIAL AND METHODS We enrolled 897 Han Chinese individuals, including 478 patients and 419 healthy controls, and detected CNVs of IL22 and LCE3C using the comparative CT method by real-time PCR, and Pearson's χ² test was used to evaluated the copy number difference among subtypes. RESULTS CNVs of IL22 were significantly higher in PsV than in healthy controls (P<0.001). CNV of LCE3C in PsV, PsA, and GPP groups were significantly lower compared to healthy controls. When linked with clinical parameters, mild psoriasis carried less IL22 copy numbers than that in severe psoriasis (P=0.043). Neither IL22 or LCE3C CNVs were associated with age of onset. CONCLUSIONS CNVs of LCE3C and IL22 might differentially contribute to subtypes of psoriasis. These findings suggest complex and diverse genetic variations in and among different clinical subtypes of psoriasis.
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Proteínas Ricas en Prolina del Estrato Córneo/genética , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Interleucinas/genética , Psoriasis/genética , Adulto , China , Femenino , Humanos , Masculino , Interleucina-22RESUMEN
PURPOSE: Cervical squamous cell carcinoma (CESC) is the most common cancer type of cervical cancer, which threatens women's life seriously. LncRNA DGUOK-AS1has been reported to promote the biologic processes of CESC. We aim to figure out the role of DGUOK-AS1-miR-499a-5p-SPRR1B axis in modulating the CESC progression in vitro. METHODS: The levels of DGUOK-AS1, miR-499a-5p, and SPRR1B in CESC tissues and cells were examined by RT-qPCR. The interaction of DGUOK-AS1-miR-499a-5p-SPRR1B was verified by luciferase assay. Inhibition of DGUOK-AS1, miR-499a-5p, and SPRR1B was applied for exploring the biological function based on detection of cell viability, proliferation, migration, and apoptosis in CESC SiHa and HeLa cells. RESULTS: DGUOK-AS1 and SPRR1B expressions were obviously elevated, whereas the expression of miR-499a-5p was reduced in both CESC tissues and cells. Silencing of DGUOK-AS1 attenuated cell growth and boosted apoptosis of CESC cells. Notably, DGUOK-AS1 inhibited miR-499a-5p to release SPRR1B, which significantly accelerated the development of CESC. CONCLUSION: DGUOK-AS1sponging miR-499a-5p facilitated CESC cells progression by releasing SPRR1B in vitro. It provides a new sight for the treatment of CESC patients involving DGUOK-AS1-miR-499a-5p-SPRR1B.
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Carcinoma de Células Escamosas/genética , Proteínas Ricas en Prolina del Estrato Córneo/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , ARN Largo no Codificante/genética , Neoplasias del Cuello Uterino/genética , Apoptosis/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Supervivencia Celular/genética , Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Progresión de la Enfermedad , Femenino , Células HeLa , Humanos , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patologíaRESUMEN
A diverse group of antimicrobial proteins (AMPs) helps protect the mammalian intestine from varied microbial challenges. We show that small proline-rich protein 2A (SPRR2A) is an intestinal antibacterial protein that is phylogenetically unrelated to previously discovered mammalian AMPs. In this study, SPRR2A was expressed in Paneth cells and goblet cells and selectively killed Gram-positive bacteria by disrupting their membranes. SPRR2A shaped intestinal microbiota composition, restricted bacterial association with the intestinal surface, and protected against Listeria monocytogenes infection. SPRR2A differed from other intestinal AMPs in that it was induced by type 2 cytokines produced during helminth infection. Moreover, SPRR2A protected against helminth-induced bacterial invasion of intestinal tissue. Thus, SPRR2A is a distinctive AMP triggered by type 2 immunity that protects the intestinal barrier during helminth infection.
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Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Microbioma Gastrointestinal , Bacterias Grampositivas/fisiología , Mucosa Intestinal/metabolismo , Intestinos/microbiología , Nematospiroides dubius , Infecciones por Strongylida/inmunología , Animales , Carga Bacteriana , Membrana Celular/metabolismo , Permeabilidad de la Membrana Celular , Proteínas Ricas en Prolina del Estrato Córneo/genética , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Células Caliciformes/metabolismo , Humanos , Inmunidad Innata , Mucosa Intestinal/microbiología , Listeria monocytogenes/fisiología , Listeriosis/microbiología , Ratones , Viabilidad Microbiana , Células de Paneth/metabolismo , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Infecciones por Strongylida/metabolismo , Infecciones por Strongylida/microbiologíaRESUMEN
Chronic postsurgical pain (CPSP) is a serious problem. We developed a mouse model of CPSP induced by electrocautery and examined the mechanism of CPSP. In this mouse model, while both incision and electrocautery each produced acute allodynia, persistent allodynia was only observed after electrocautery. Under these conditions, we found that the mRNA levels of Small proline rich protein 1A (Sprr1a) and Annexin A10 (Anxa10), which are the key modulators of neuropathic pain, in the spinal cord were more potently and persistently increased by electrocautery than by incision. Furthermore, these genes were overexpressed almost exclusively in chronic postsurgical pain-activated neurons. This event was associated with decreased levels of tri-methylated histone H3 at Lys27 and increased levels of acetylated histone H3 at Lys27 at their promoter regions. On the other hand, persistent allodynia and overexpression of Sprr1a and Anxa10 after electrocautery were dramatically suppressed by systemic administration of GSK-J4, which is a selective H3K27 demethylase inhibitor. These results suggest that the effects of electrocautery contribute to CPSP along with synaptic plasticity and epigenetic modification.
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Anexinas/biosíntesis , Proteínas Ricas en Prolina del Estrato Córneo/biosíntesis , Electrocoagulación/efectos adversos , Código de Histonas , Hiperalgesia/etiología , Proteínas del Tejido Nervioso/biosíntesis , Neuralgia/genética , Neuronas/fisiología , Dolor Postoperatorio/genética , Médula Espinal/fisiopatología , Animales , Anexinas/genética , Benzazepinas/farmacología , Benzazepinas/uso terapéutico , Proteínas Ricas en Prolina del Estrato Córneo/genética , Modelos Animales de Enfermedad , Femenino , Traumatismos de los Pies/fisiopatología , Regulación de la Expresión Génica , Técnicas de Sustitución del Gen , Genes Reporteros , Genes fos , Histonas/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Lisina/metabolismo , Masculino , Metilación , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Neuralgia/tratamiento farmacológico , Neuralgia/fisiopatología , Neuronas/efectos de los fármacos , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/fisiopatología , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologíaRESUMEN
The turnover of the epidermis beginning with the progenitor cells in the basal layer to the fully differentiated corneocytes is tightly regulated by calcium. Calcium more than anything else promotes the differentiation of keratinocytes which implies the need for a calcium gradient with low concentrations in the stratum basale and high concentrations in the stratum granulosum. One of the hallmarks of skin aging is a collapse of this gradient that has a direct impact on the epidermal fitness. The rise of calcium in the stratum basale reduces cell proliferation, whereas the drop of calcium in the stratum granulosum leads to a changed composition of the cornified envelope. We showed that keratinocytes respond to the calcium induced block of cell division by a large increase of the expression of several miRNAs (hsa-mir542-5p, hsa-mir125a, hsa-mir135a-5p, hsa-mir196a-5p, hsa-mir491-5p and hsa-mir552-5p). The pitfall of this rescue mechanism is a dramatic change in gene expression which causes a further impairment of the epidermal barrier. This effect is attenuated by a pseudogene (SPRR2C) that gives rise to a lncRNA. SPRR2C specifically resides in the stratum granulosum/corneum thus acting as a sponge for miRNAs.
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Calcio/metabolismo , Proteínas Ricas en Prolina del Estrato Córneo/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Envejecimiento de la Piel/genética , Diferenciación Celular/fisiología , Proliferación Celular , Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Células Epidérmicas/metabolismo , Expresión Génica , Humanos , Queratinocitos/citología , MicroARNs/metabolismoRESUMEN
MicroRNA-150 (miR-150) is downregulated in patients with multiple cardiovascular diseases and in diverse mouse models of heart failure (HF). miR-150 is significantly associated with HF severity and outcome in humans. We previously reported that miR-150 is activated by ß-blocker carvedilol (Carv) and plays a protective role in the heart using a systemic miR-150 KO mouse model. However, mechanisms that regulate cell-specific miR-150 expression and function in HF are unknown. Here, we demonstrate that potentially novel conditional cardiomyocyte-specific (CM-specific) miR-150 KO (miR-150 cKO) in mice worsens maladaptive cardiac remodeling after myocardial infarction (MI). Genome-wide transcriptomic analysis in miR-150 cKO mouse hearts identifies small proline-rich protein 1a (Sprr1a) as a potentially novel target of miR-150. Our studies further reveal that Sprr1a expression is upregulated in CMs isolated from ischemic myocardium and subjected to simulated ischemia/reperfusion, while its expression is downregulated in hearts and CMs by Carv. We also show that left ventricular SPRR1A is upregulated in patients with HF and that Sprr1a knockdown in mice prevents maladaptive post-MI remodeling. Lastly, protective roles of CM miR-150 are, in part, attributed to the direct and functional repression of proapoptotic Sprr1a. Our findings suggest a crucial role for the miR-150/SPRR1A axis in regulating CM function post-MI.
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Proteínas Ricas en Prolina del Estrato Córneo/genética , MicroARNs/genética , MicroARNs/metabolismo , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Remodelación Ventricular/genética , Antagonistas Adrenérgicos beta/farmacología , Animales , Apoptosis/fisiología , Carvedilol/farmacología , Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Regulación hacia Abajo , Femenino , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/metabolismo , Humanos , Masculino , Ratones , Ratones Noqueados , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Regulación hacia ArribaRESUMEN
Functional studies to delineate the molecular mechanisms of causal genetic variants are the main focus in the post-GWAS era. Previous GWASs have identified >50 susceptibility loci associated with psoriasis. Functional understanding of the biology underlying the disease risk of most of these associated loci is unclear. In this study, we identified a regulatory SNP at the putative enhancer of the LCE3A gene within the epidermal differentiation complex that showed epistatic interaction with HLA-Cw6. The variant allele disrupted signal transducer and activator of transcription 3 binding to the region, thereby regulating the expression of the downstream LCE3A gene. Electrophoretic mobility shift and pulldown assay confirmed the preferential binding of signal transducer and activator of transcription 3 to the DNA with a wild-type allele compared with the DNA with a variant allele. The reporter assay further validated the IL-6âstimulated phosphorylated signal transducer and activator of transcription 3âmediated LCE3A activation in the presence of the wild-type allele. Interestingly, the presence of the HLA-Cw6 allele leads to IL-6âmediated phosphorylation of signal transducer and activator of transcription 3, followed by its nuclear localization in the epidermal keratinocytes of psoriatic skin, suggesting indirect interaction of the HLA-Cw6 allele and a regulatory SNP upstream of the LCE3A gene. This study reflects an interesting approach to dissecting the molecular mechanism underlying the genetic interaction observed between HLA-Cw6 and LCE3A in psoriasis pathogenesis.
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Proteínas Ricas en Prolina del Estrato Córneo/genética , Antígenos HLA-C/genética , Psoriasis/genética , Células Cultivadas , Regulación de la Expresión Génica , Humanos , Interleucina-1alfa/fisiología , Interleucina-6/fisiología , Fosforilación , Polimorfismo de Nucleótido Simple , Psoriasis/etiología , Factor de Transcripción STAT3/metabolismoRESUMEN
The aim of this study was to examine the effects of carba cyclic phosphatidic acid (ccPA) on cornified envelope (CE) formation and keratinocyte differentiation. ccPA-treated keratinocytes showed higher mRNA and protein levels of differentiation markers and CE components than untreated cells. These results suggest that ccPA could serve as therapeutic targets for treating skin barrier dysfunction because of their roles in upregulating genes and proteins associated with CE formation and keratinocyte differentiation.
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Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Queratinocitos/efectos de los fármacos , Ácidos Fosfatidicos/farmacología , Diferenciación Celular/efectos de los fármacos , Línea Celular , Proteínas Ricas en Prolina del Estrato Córneo/genética , Expresión Génica/efectos de los fármacos , Humanos , Queratinocitos/citología , Queratinocitos/metabolismoRESUMEN
Cutaneous squamous cell carcinoma (cSCC) is prevalent in the world, accounting for a huge part of non-melanoma skin cancer. Most cSCCs are associated with a distinct pre-cancerous lesion, the actinic keratosis (AK). However, the progression trajectory from normal skin to AK and cSCC has not been fully demonstrated yet. To identify genes involved in this progression trajectory and possible therapeutic targets for cSCC, here we constructed a UV-induced cSCC mouse model covering the progression from normal skin to AK to cSCC, which mimicked the solar UV radiation perfectly using the solar-like ratio of UVA and UVB, firstly. Then, transcriptome analysis and a series of bioinformatics analyses and cell experiments proved that Rorα is a key transcript factor during cSCC progression. Rorα could downregulate the expressions of S100a9 and Sprr2f in cSCC cells, which can inhibit the proliferation and migration in cSCC cells, but not the normal keratinocyte. Finally, further animal experiments confirmed the inhibitory effect of cSCC growth by Rorα in vivo. Our findings showed that Rorα would serve as a potential novel target for cSCC, which will facilitate the treatment of cSCC in the future.
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Carcinoma de Células Escamosas/metabolismo , Transformación Celular Neoplásica/metabolismo , Queratosis Actínica/metabolismo , Neoplasias Inducidas por Radiación/metabolismo , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/deficiencia , Neoplasias Cutáneas/metabolismo , Animales , Calgranulina B/genética , Calgranulina B/metabolismo , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Proteínas Ricas en Prolina del Estrato Córneo/genética , Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Queratosis Actínica/etiología , Queratosis Actínica/genética , Queratosis Actínica/patología , Ratones Pelados , Invasividad Neoplásica , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/patología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Factores de Transcripción de Octámeros/genética , Factores de Transcripción de Octámeros/metabolismo , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Transcriptoma , Rayos UltravioletaRESUMEN
OBJECTIVE: Atopic eczema (AE) is a chronic relapsing inflammatory skin disease. This study aims to identify key genes related to the development of AE. MATERIALS AND METHODS: The GSE6012 dataset was obtained from the Gene Expression Omnibus (GEO) database. The limma package was used to analyze differentially expressed genes (DEGs). Then, the weighted gene co-expression network analysis (WGCNA) package was utilized to generate weighted correlation networks of up-and downregulated genes. Additionally, the WGCNA package was used for enrichment analyses to explore the underlying functions of DEGs in modules (weighted correlation sub-networks) significantly associated with AE. RESULTS: A total of 515 DEGs were identified between lesional and non-lesional skin samples. For the upregulated genes, the blue module was found to have a significant positive correlation with AE. Importantly, small proline-rich protein 2C (SPRR2C) and defensin, beta 4A (DEFB4A) exhibited higher |log fold change (FC) values and were the key nodes of the network. Moreover, KEGG pathway analysis revealed that the upregulated genes in the blue module were primarily involved in cytokine-cytokine receptor interaction. Additionally, for the downregulated genes, the brown module was found to have a significant positive correlation with AE. Further, WNT inhibitory factor 1 (WIF1), cryptochrome 2 (CRY2), and keratin 19 (KRT19) had higher |log FC| values and were key nodes of the network. CONCLUSIONS: SPRR2C, DEFB4A, WIF1, CRY2, KRT19 and cytokine-cytokine receptor interaction might be correlated with the development of AE.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Ricas en Prolina del Estrato Córneo/genética , Criptocromos/genética , Dermatitis Atópica/genética , Queratina-19/genética , beta-Defensinas/genética , Citocinas/genética , Humanos , Receptores de Citocinas/genéticaRESUMEN
PURPOSE: Transport and Golgi organization protein 1 (TANGO) promotes angiogenesis and lymphangiogenesis in oral squamous cell carcinoma (OSCC). To elucidate the underlying mechanisms, this study aims to identify and characterize elements downstream of TANGO that mediate its involvement in OSCC. METHODS: In this study, microarray analysis compared gene expression between control and TANGO-repressed HSC3 cells. Protein expression in 213 OSCC tissue samples was analyzed immunohistochemically. RESULTS: TANGO repression decreased or increased expression of Mucin 20 (MUC20) and small proline-rich protein 1B (SPRR1B), respectively. MUC20 increased the growth and invasiveness of OSCC cells via altered matrix metalloproteinase (MMP)-2 and E-cadherin expression and c-met phosphorylation. MUC20 induced angiogenesis and lymphangiogenesis by activating vascular endothelial growth factors A and C. In well-differentiated OSCC, SPRR1B expression was high (P = 0.0091) and correlated with keratinization markers and promoted proliferation by inducing mitogen-activated protein kinase p38 phosphorylation. MUC20 expression correlated significantly with clinical stage (P = 0.0024), lymph node metastasis (P = 0.0036), and number of blood and lymph vessels (P < 0.0001). MUC20-expressing cases had a significantly worse prognosis than non-expressing cases (P < 0.0001). CONCLUSION: MUC20 and SPRR1B located downstream of TANGO may be useful molecular markers for OSCC.
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Translocador Nuclear del Receptor de Aril Hidrocarburo/fisiología , Biomarcadores de Tumor/aislamiento & purificación , Proteínas Ricas en Prolina del Estrato Córneo , Mucinas , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas , Células Cultivadas , Proteínas Ricas en Prolina del Estrato Córneo/genética , Proteínas Ricas en Prolina del Estrato Córneo/aislamiento & purificación , Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inmunohistoquímica , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Neoplasias de la Boca , Mucina 2/genética , Mucina 2/aislamiento & purificación , Mucina 2/metabolismo , Mucinas/genética , Mucinas/aislamiento & purificación , Mucinas/metabolismo , Transducción de Señal/genéticaRESUMEN
BACKGROUND: With the ongoing development of targeted therapy and immunotherapy in recent years, the overall five-year survival rate of NSCLC patients has not improved, and the search for novel diagnostic and prognostic markers for lung adenocarcinoma continues. METHODS: Lung adenocarcinoma (LUAD) gene expression data and relevant clinical information were obtained from the TCGA. Hub genes were identified with weighted gene co-expression network analysis (WGCNA) and protein-protein interaction network (PPI). Survival analyses were also performed using GEPIA. The 536 LUAD patients were divided into two groups according to the SPRR1B expression level and analyzed by gene set enrichment analysis (GSEA) and verified by immunoblotting. The effects of SPRR1B on cell proliferation and cell metastasis and apoptosis were evaluated by 5-ethynyl-2'-deoxyuridine (EdU) staining, colony formation assay, transwell migration and invasion assay, and flow cytometry, respectively. RESULTS: A total of 2269 DEGs were analyzed by WGCNA and five hub genes (CCK, FETUB, PCSK9, SPRR1B, and SPRR2D) were identified. Among them, SPRR1B was selected as one of the most significant prognostic genes in LUAD. SPRR1B was found to be highly expressed in lung adenocarcinoma cells compared with that in normal bronchial epithelial cells. In addition, silencing of SPRR1B could inhibit the cell proliferation, invasion, and migration of lung adenocarcinoma cells, but induced cell apoptosis and G2/M phase arrest in vitro. The result of GSEA and immunoblotting revealed that SPRR1B activated the MAPK signaling pathway involved in the proliferation and metastasis of lung cancer. CONCLUSIONS: Our findings demonstrate that SPRR1B may function as a prognosis predictor in lung adenocarcinoma.
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Adenocarcinoma del Pulmón/metabolismo , Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Apoptosis/fisiología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular/fisiología , Biología Computacional/métodos , Proteínas Ricas en Prolina del Estrato Córneo/genética , Femenino , Humanos , Masculino , PronósticoRESUMEN
Psoriasis is a chronic inflammatory disease of the skin with highly complex pathogenesis. In this study, we identified lncRNA SPRR2C (small proline-rich protein 2C) as a hub gene with a critical effect on the pathogenesis of psoriasis and response to treatment using both weighted gene coexpression network analysis (WGCNA) and differential expression analysis. SPRR2C expression was significantly upregulated in both psoriatic lesion samples and HaCaT cell lines in response to IL-22 treatment. After SPRR2C knockdown, IL-22-induced suppression of HaCaT proliferation, changes in the KRT5/14/1/10 protein levels, and suppression of the IL-1ß, IL-6, and TNF-α mRNA levels were dramatically reversed. In the coexpression network with SPRR2C based on GSE114286, miR-330 was significantly negatively correlated with SPRR2C, while STAT1 and S100A7 were positively correlated with SPRR2C. By binding to miR-330, SPRR2C competed with STAT1 and S100A7 to counteract miR-330-mediated suppression of STAT1 and S100A7. MiR-330 overexpression also reversed the IL-22-induced changes in HaCaT cell lines; in response to IL-22 treatment, miR-330 inhibition significantly attenuated the effects of SPRR2C knockdown. STAT1 and S100A7 expression was significantly upregulated in psoriatic lesion samples. The expression of miR-330 had a negative correlation with the expression of SPRR2C, while the expression of SPRR2C had a positive correlation with the expression of STAT1 and S100A7. Thus, SPRR2C modulates the IL-22-stimulated HaCaT cell phenotype through the miR-330/STAT1/S100A7 axis. WGCNA might uncover additional biological pathways that are crucial in the pathogenesis and response to the treatment of psoriasis.