Assuntos
Adenocarcinoma , Biomarcadores Tumorais , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/imunologia , Prognóstico , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Biomarcadores Tumorais/imunologia , Proteínas S100/imunologiaRESUMO
S100A1, a calcium-binding protein, plays a crucial role in regulating Ca2+ signaling pathways in skeletal and cardiac myocytes via interactions with the ryanodine receptor (RyR) to affect Ca2+ release and contractile performance. Biophysical studies strongly suggest that S100A1 interacts with RyRs but have been inconclusive about both the nature of this interaction and its competition with another important calcium-binding protein, calmodulin (CaM). Thus, high-resolution cryo-EM studies of RyRs in the presence of S100A1, with or without additional CaM, were needed. The elegant work by Weninger et al. demonstrates the interaction between S100A1 and RyR1 through various experiments and confirms that S100A1 activates RyR1 at sub-micromolar Ca2+ concentrations, increasing the open probability of RyR1 channels.
Assuntos
Canal de Liberação de Cálcio do Receptor de Rianodina , Proteínas S100 , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Humanos , Animais , Proteínas S100/metabolismo , Proteínas S100/química , Cálcio/metabolismo , Calmodulina/metabolismoRESUMO
Baicalin is a flavonoid extracted from Scutellaria baicalensis Georgi. As it has significant antitumor and apoptosis-inducing effects, baicalin may be useful as a lead compound in new antitumor drug development. However, as the pharmacological actions of baicalin have yet to be elucidated, we isolated its target protein, which was successfully identified as Annexin A2. Annexin A2 forms a heterotetramer with S100A10 protein, which plays an important role in the plasminogen activator system. The heterotetramer bound to tissue plasminogen activator (tPA) activates the conversion of plasminogen to plasmin and promotes the expression of STAT-3 and NF-κB, which are target genes involved in the development of cancer. Moreover, NF-κB and STAT-3 induce the expression of cell inhibitors of apoptotic proteins and inhibit apoptosis. To examine whether these antitumor and apoptosis-inducing effects of baicalin are mediated by Annexin A2, we prepared Annexin A2 knockdown HepG2 cells. We compared mRNA expression by RT-qPCR and apoptosis by caspase-3 activity assays in Annexin A2 knockdown HepG2 cells. The results showed that the antitumor and apoptosis-inducing effects of baicalin are mediated by Annexin A2. The results of this study suggest that agents capable of inhibiting Annexin A2 may be useful candidates for the development of novel antitumor agents.
Assuntos
Anexina A2 , Antineoplásicos , Apoptose , Flavonoides , Anexina A2/metabolismo , Anexina A2/genética , Humanos , Flavonoides/farmacologia , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Células Hep G2 , Fator de Transcrição STAT3/metabolismo , NF-kappa B/metabolismo , Técnicas de Silenciamento de Genes , Proteínas S100/metabolismo , Proteínas S100/genética , Scutellaria baicalensis/químicaRESUMO
Granular cell tumours (GCT) of the breast have similar clinical and radiological features to breast carcinomas. We present a case of a female patient with a tender, palpable lump, and associated skin changes. Imaging of the lesion was suspicious of malignancy. Initial histological examination showed uniform sheets of polygonal cells with abundant granular cytoplasm, and follow-up immunohistochemistry showed strongly positive staining of tumour cells with S100 and CD68, confirming the diagnosis of GCT. Wide local excision with complete resection margins was performed as a curative treatment for this lesion. This case report highlights the importance of considering GCTs in the differential diagnoses of breast lesions suspicious of malignancy and emphasises the necessity of accurate diagnosis of GCT for proper treatment.
Assuntos
Neoplasias da Mama , Tumor de Células Granulares , Humanos , Feminino , Tumor de Células Granulares/patologia , Tumor de Células Granulares/cirurgia , Tumor de Células Granulares/diagnóstico por imagem , Tumor de Células Granulares/diagnóstico , Neoplasias da Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Diagnóstico Diferencial , Imuno-Histoquímica , Adulto , Mamografia , Proteínas S100/análise , Proteínas S100/metabolismo , Mama/patologia , Mama/diagnóstico por imagem , Pessoa de Meia-IdadeRESUMO
Icariside II, a flavonoid glycoside, is the main component found invivo after the administration of Herba epimedii and has shown some pharmacological effects, such as prevention of osteoporosis and enhancement of immunity. Increased levels of marrow adipose tissue are associated with osteoporosis. S100 calcium-binding protein A16 (S100A16) promotes the differentiation of bone marrow mesenchymal stem cells (BMSCs) into adipocytes. This study aimed to confirm the anti-lipidogenesis effect of Icariside II in the bone marrow by inhibiting S100A16 expression. We used ovariectomy (OVX) and BMSC models. The results showed that Icariside II reduced bone marrow fat content and inhibited BMSCs adipogenic differentiation and S100A16 expression, which correlated with lipogenesis. Overexpression of S100A16 eliminated the inhibitory effect of Icariside II on lipid formation. ß-catenin participated in the regulation adipogenesis mediated by Icariside II/S100A16 in the bone. In conclusion, Icariside II protects against OVX-induced bone marrow adipogenesis by downregulating S100A16, in which ß-catenin might also be involved.
Assuntos
Adipogenia , Tecido Adiposo , Estrogênios , Flavonoides , Células-Tronco Mesenquimais , Ovariectomia , Animais , Adipogenia/efeitos dos fármacos , Feminino , Tecido Adiposo/metabolismo , Tecido Adiposo/efeitos dos fármacos , Flavonoides/farmacologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Estrogênios/metabolismo , Estrogênios/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proteínas S100/metabolismo , Proteínas S100/genética , Medula Óssea/metabolismo , Medula Óssea/efeitos dos fármacos , beta Catenina/metabolismo , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacosRESUMO
Objective: To investigate the clinical, cytomorphology, immunocytochemical and molecular features of metastatic melanoma in serosal cavity effusion. Methods: Cytological specimens of 14 patients with melanoma in the chest and abdomen were collected from 2017 to 2023, at the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. SOX10, S-100 protein, PRAME, BRAF V600E, HMB45, and Melan A were detected by immunocytochemical methods. Fourteen cases were tested for routine antibody combinations, including Claudin4, HEG1, Calretinin, CD68, etc. Four of the patients had biopsy or surgical samples of metastatic solid lesions of primary sites, and further next-generation sequencing (NGS) or amplification refractory mutation system (ARMS)-PCR molecular test was performed. In addition, 30 cases of serosal effusion samples were collected as control groups (10 cases of benign mesothelial cell reactive hyperplasia, 10 cases of mesothelioma, and 10 cases of metastatic lung adenocarcinoma). Results: Among the 14 cases of melanoma, there were 7 males and 7 females, with ages ranging from 35 to 86 years, and an average age of 57 years, there 10 cases aged ≥50 years. The tumor cells in the serosal effusion varied in morphology and degree of atypia. SOX10 was positive in all 14 cases (14/14), S-100 protein was positive in 10 cases (10/14), PRAME was positive in 12 cases (12/14), BRAF V600E was positive in 10 cases (10/14), HMB45 was positive in 12 cases (12/14), and Melan A was positive in 13 cases (13/14). In 4 patients with histological correlation, the cytological and histological expression of SOX10, BRAF V600E, and PRAME was positive in all 4 cases (4/4); S-100 protein was positive in 2 cases (2/4); and HMB45 and Melan A were positive in 3 cases (3/4). Using NGS or ARMS-PCR, missense mutations of BRAF V600E were detected in all 4 patients; TERT promoter mutations was detected in 1 case; and CDKN2A terminating mutations and MSI1 deletion mutations were detected in the other case. SOX10, S-100, HMB45, Melan A, PRAME and BRAF V600E were all negative in 30 control samples of serosal cavity effusion. Conclusion: By observing the morphology of tumor cells, immunocytochemical test of several combination markers, especially the expression of SOX10, BRAF V600E and PRAME, can help to improve the positive diagnosis rate of melanoma in serous cavity effusion.
Assuntos
Melanoma , Proteínas Proto-Oncogênicas B-raf , Proteínas S100 , Fatores de Transcrição SOXE , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antígenos de Neoplasias , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Antígeno gp100 de Melanoma , Sequenciamento de Nucleotídeos em Larga Escala , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Antígeno MART-1/metabolismo , Melanoma/patologia , Melanoma/metabolismo , Melanoma/genética , Melanoma/secundário , Antígenos Específicos de Melanoma/metabolismo , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas S100/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/genética , Fatores de Transcrição SOXE/metabolismo , Fatores de Transcrição SOXE/genéticaRESUMO
S100 proteins comprise a family of structurally related proteins that are calcium-sensitive. S100 proteins have been found to play various roles in regulation of cell apoptosis, cell proliferation and differentiation, cell migration and invasion, energy metabolism, calcium homeostasis, protein phosphorylation, anti-microbial activity and inflammation in a variety of cell types. While the specific function of many S100 proteins remains unknown, some of the S100 proteins serve as disease biomarkers as well as possible therapeutic targets in skin diseases. Interface dermatitis (ID) is a histopathological term that covers many different skin conditions including cutaneous lupus erythematosus, lichen planus, and dermatomyositis. These pathologies share similar histological features, which include basal cell vacuolization and lymphocytic infiltration at the dermal-epidermal junction. In this review, we summarize how the S100 protein family contributes to both homeostatic and inflammatory processes in the skin. We also highlight the role of S100 proteins in neuronal signalling, describing how this might contribute to neuroimmune interactions in ID and other skin pathologies. Last, we discuss what is known about the S100 family proteins as both biomarkers and potential treatment targets in specific pathologies.
Assuntos
Homeostase , Proteínas S100 , Pele , Humanos , Proteínas S100/metabolismo , Pele/metabolismo , Pele/patologia , Dermatite/metabolismo , Dermatopatias/metabolismo , Biomarcadores/metabolismo , AnimaisRESUMO
There is a significant difference in prognosis and response to chemotherapy between basal and classical subtypes of pancreatic ductal adenocarcinoma (PDAC). Further biomarkers are required to identify subtypes of PDAC. We selected candidate biomarkers via review articles. Correlations between these candidate markers and the PDAC molecular subtype gene sets were analyzed using bioinformatics, confirming the biomarkers for identifying classical and basal subtypes. Subsequently, 298 PDAC patients were included, and their tumor tissues were immunohistochemically stratified using these biomarkers. Survival data underwent analysis, including Cox proportional hazards modeling. Our results indicate that the pairwise and triple combinations of KRT5/KRT17/S100A2 exhibit a higher correlation coefficient with the basal-like subtype gene set, whereas the corresponding combinations of GATA6/HNF4A/TFF1 show a higher correlation with the classical subtype gene set. Whether analyzing unmatched or propensity-matched data, the overall survival time was significantly shorter for the basal subtype compared with the classical subtype (p < .001), with basal subtype patients also facing a higher risk of mortality (HR = 4.017, 95% CI 2.675-6.032, p < .001). In conclusion, the combined expression of KRT5, KRT17, and S100A2, in both pairwise and triple combinations, independently predicts shorter overall survival in PDAC patients and likely identifies the basal subtype. Similarly, the combined expression of GATA6, HNF4A, and TFF1, in the same manner, may indicate the classical subtype. In our study, the combined application of established biomarkers offers valuable insights for the prognostic evaluation of PDAC patients.
Assuntos
Biomarcadores Tumorais , Carcinoma Ductal Pancreático , Queratina-17 , Queratina-5 , Neoplasias Pancreáticas , Proteínas S100 , Humanos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Masculino , Feminino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Pessoa de Meia-Idade , Proteínas S100/genética , Proteínas S100/metabolismo , Queratina-5/genética , Queratina-5/metabolismo , Idoso , Queratina-17/genética , Queratina-17/metabolismo , Prognóstico , Fator de Transcrição GATA6/genética , Fator de Transcrição GATA6/metabolismo , Regulação Neoplásica da Expressão Gênica , Adulto , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Fatores QuimiotáticosRESUMO
Hepatocellular carcinoma (HCC) is a common malignant tumor with a complex immune evasion mechanism posing a challenge to treatment. The role of the S100A10 gene in various cancers has garnered significant attention. This study aims to elucidate the impact of S100A10 on CD8+ T cell exhaustion via the cPLA2 and 5-LOX axis, thereby elucidating its role in immune evasion in HCC. By analyzing the HCC-related data from the GEO and TCGA databases, we identified differentially expressed genes associated with lipid metabolism and developed a prognostic risk model. Subsequently, through RNA-seq and PPI analyses, we determined vital lipid metabolism genes and downstream factors S100A10, ACOT7, and SMS, which were significantly correlated with CD8+ T cell infiltration. Given the most significant expression differences, we selected S100A10 for further investigation. Both in vitro and in vivo experiments were conducted, including co-culture experiments of CD8+ T cells with MHCC97-L cells, Co-IP experiments, and validation in an HCC mouse model. S100A10 was significantly overexpressed in HCC tissues and potentially regulates CD8+ T cell exhaustion and lipid metabolism reprogramming through the cPLA2 and 5-LOX axis. Silencing S100A10 could inhibit CD8+ T cell exhaustion, further suppressing immune evasion in HCC. S100A10 may activate the cPLA2 and 5-LOX axis, initiating lipid metabolism reprogramming and upregulating LTB4 levels, thus promoting CD8+ T cell exhaustion in HCC tissues, facilitating immune evasion by HCC cells, ultimately impacting the growth and migration of HCC cells. This research highlights the critical role of S100A10 via the cPLA2 and 5-LOX axis in immune evasion in HCC, providing new theoretical foundations and potential targets for diagnosing and treating HCC.
Assuntos
Araquidonato 5-Lipoxigenase , Linfócitos T CD8-Positivos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Evasão Tumoral , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Humanos , Animais , Camundongos , Araquidonato 5-Lipoxigenase/metabolismo , Araquidonato 5-Lipoxigenase/genética , Linhagem Celular Tumoral , Proteínas S100/metabolismo , Proteínas S100/genética , Fosfolipases A2 Citosólicas/metabolismo , Fosfolipases A2 Citosólicas/genética , Masculino , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos C57BL , Exaustão das Células TRESUMO
BACKGROUND: To improve the characteristics of primary thyroid schwannomas (PTS) and to provide reference basis for clinical diagnosis and treatment. METHODS: PubMed was searched for case reports of PTS up to December 2022 using the search terms "Thyroid nerve sheath tumor" or "Thyroid schwannoma" or "Thyroid Neurilemmoma", respectively. 34 cases were screened. RESULTS: PTS can occur at any age, nodules averaged 3.9 cm. The most common symptoms were voice change and dysphagia. Fine needle aspiration cytology showing spindle-shaped cells should be considered for schwannoma. Most cases underwent thyroid lobectomy or nodule removal with a good prognosis. Tissue types with both Antoni A and Antoni B features are common. Positive immunohistochemical staining for S-100 protein, CD34 and waveform proteins helped confirm the diagnosis. CONCLUSIONS: Positive immunohistochemistry for S-100 and wave proteins helps confirm the diagnosis. Preoperative diagnosis is challenging, but pathology and immunohistochemical staining are the gold standard for diagnosis. The first choice of treatment is surgical resection of the nodules, the prognosis is good.
Assuntos
Neurilemoma , Neoplasias da Glândula Tireoide , Humanos , Neurilemoma/diagnóstico , Neurilemoma/cirurgia , Neurilemoma/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Biópsia por Agulha Fina , Imuno-Histoquímica , Idoso , Proteínas S100/metabolismo , Proteínas S100/análise , Tireoidectomia , Glândula Tireoide/patologia , Glândula Tireoide/cirurgia , PrognósticoRESUMO
BACKGROUND: Lung adenocarcinoma (LUAD) is a fatal disease with metabolic abnormalities. The dysregulation of S100 calcium-binding protein A2 (S100A2), a member of the S100 protein family, is connected to the development of various cancers. The impact of S100A2 on the LUAD occurrence and metastasis, however, has not yet been reported. The functional mechanism of S100A2 on LUAD cell metastasis was examined in this article. METHODS: The expression of TFAP2A and S100A2 in LUAD tissues and cells was analyzed by bioinformatics and qRT-PCR, respectively. The enrichment pathway analysis was performed on S100A2. Bioinformatics analysis determined the binding relationship between TFAP2A and S100A2, and their interaction was validated through dual-luciferase and chromatin immunoprecipitation experiments. Cell viability was determined using cell counting kit-8 (CCK-8). A transwell assay was performed to analyze the invasion and migration of cells. Immunofluorescence was conducted to obtain vimentin and E-cadherin expression, and a western blot was used to detect the expression of MMP-2, MMP-9, GLS, and GLUD1. The kits measured the NADPH/NADP ratio, glutathione (GSH)/glutathione disulfide (GSSG) levels, and the contents of glutamine, α-KG, and glutamate. RESULTS: S100A2 was upregulated in LUAD tissues and cells, and S100A2 mediated glutamine metabolism to induce LUAD metastasis. Additionally, the transcriptional regulator TFAP2A was discovered upstream of S100A2, and TFAP2A expression was upregulated in LUAD, which indicated that TFAP2A promoted the S100A2 expression. The rescue experiment found that upregulation of S100A2 could reverse the inhibitory effects of silencing TFAP2A on glutamine metabolism and cell metastasis. CONCLUSION: In conclusion, by regulating glutamine metabolism, the TFAP2A/S100A2 axis facilitated LUAD metastasis. This suggested that targeting S100A2 could be beneficial for LUAD treatment.
Assuntos
Adenocarcinoma de Pulmão , Glutamina , Neoplasias Pulmonares , Proteínas S100 , Fator de Transcrição AP-2 , Humanos , Fator de Transcrição AP-2/metabolismo , Fator de Transcrição AP-2/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/secundário , Glutamina/metabolismo , Proteínas S100/metabolismo , Proteínas S100/genética , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Movimento Celular , Metástase Neoplásica , Masculino , Regulação para Cima , Feminino , Proliferação de Células , Fatores QuimiotáticosRESUMO
BACKGROUND/AIMS: The S100 family contains more than 20 Ca2+-binding proteins that participate in numerous cellular biological processes. However, the prognostic value of individual S100s in hepatocellular carcinoma (HCC) remains unclear. Therefore, we comprehensively assessed the prognostic value of S100s in HCC. MATERIALS AND METHODS: The mRNA level of S100s in distinct types of cancer was analyzed through Oncomine. The clinical prognostic significance of each S100 was evaluated using Kaplan-Meier plotter and OncoLnc. The expression and mutation of S100s were determined through cBioPortal. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to predict the functions and pathways of S100s. RESULTS: The analyses revealed that, relative to normal tissues, liver cancer tissues showed aberrant mRNA expression of most S100s. In the survival analysis with Kaplan-Meier plotter, elevated expression levels of S100PBP, S100A2, S100A7, S100A10, and S100A13 were related to shorter overall survival (OS), whereas increased S100A5 expression was associated with longer OS. Moreover, results obtained using OncoLnc showed that increased expression levels of S100P, S100PBP, S100A13, S100A11, S100A10, and S100A2 were related to shorter OS. Thus, S100PBP, S100A13, S100A10, and S100A2 exhibited the same prognostic trend in the 2 databases. However, all S100 member gene mutational changes had no considerable prognostic value in OS and disease-free survival of HCC patients. CONCLUSION: Although the findings need to be further confirmed by experiments, they provide new evidence for the prognostic significance of the S100s in HCC.
Assuntos
Carcinoma Hepatocelular , Estimativa de Kaplan-Meier , Neoplasias Hepáticas , RNA Mensageiro , Proteínas S100 , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Proteínas S100/genética , Prognóstico , RNA Mensageiro/metabolismo , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Feminino , Masculino , Mutação , Análise de SobrevidaRESUMO
Many researchers have focused on the role of the autonomic nervous system in the tumor microenvironment. Autonomic nerves include the sympathetic and parasympathetic nerves, which are known to induce cancer growth and metastasis. However, in salivary duct carcinoma (SDC), a rare and highly malignant tumor, the issue should be investigated from both biological and therapeutic perspectives. We explored the clinicopathological and prognostic implications of the autonomic nerves in 129 SDCs. Immunohistochemistry was performed to determine the nature of each nerve using antibodies against S100, tyrosine hydroxylase (TH) as a sympathetic marker, and vesicular acetylcholine transporter (VAChT) as a parasympathetic marker. The area of each marker-positive nerve was digitized and evaluated quantitatively. Double immunofluorescence for TH and VAChT was performed in selected cases. The expression of the secreted neurotrophins was also examined. S100-positive nerves were present in the cancer tissue in 94 of 129 cases (72.9%). Among them, TH-positive sympathetic nerves and/or VAChT-positive parasympathetic nerves were identified in 92 cases (97.9%), and 59 cases (62.8%) had TH/VAChT-co-expressing nerves. Double immunofluorescence revealed a mosaic pattern of sympathetic and parasympathetic fibers in co-expressing nerve bundles. The presence of autonomic nerves, regardless of their area, was significantly associated with aggressive histological features, advanced T/N classification, and a poor prognosis, with shorter disease-free and overall survival. There was an association between some tumor immune microenvironment-related markers and the autonomic nerve status, but not the latter and the secreted neurotrophin expression. This study suggests that autonomic nerves might play a role in the progression of SDC.
Assuntos
Neoplasias das Glândulas Salivares , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Prognóstico , Neoplasias das Glândulas Salivares/patologia , Neoplasias das Glândulas Salivares/metabolismo , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Ductos Salivares/patologia , Ductos Salivares/inervação , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Tirosina 3-Mono-Oxigenase/análise , Imuno-Histoquímica , Vias Autônomas/patologia , Sistema Nervoso Autônomo/patologia , Sistema Nervoso Autônomo/metabolismo , Carcinoma Ductal/patologia , Proteínas S100/metabolismo , Proteínas S100/análise , Microambiente TumoralRESUMO
Plasma membrane repair is a fundamental homeostatic process of eukaryotic cells. Here, we report a new function for the conserved cytoskeletal proteins known as septins in the repair of cells perforated by pore-forming toxins or mechanical disruption. Using a silencing RNA screen, we identified known repair factors (e.g. annexin A2, ANXA2) and novel factors such as septin 7 (SEPT7) that is essential for septin assembly. Upon plasma membrane injury, the septin cytoskeleton is extensively redistributed to form submembranous domains arranged as knob and loop structures containing F-actin, myosin IIA, S100A11, and ANXA2. Formation of these domains is Ca2+-dependent and correlates with plasma membrane repair efficiency. Super-resolution microscopy revealed that septins and F-actin form intertwined filaments associated with ANXA2. Depletion of SEPT7 prevented ANXA2 recruitment and formation of submembranous actomyosin domains. However, ANXA2 depletion had no effect on domain formation. Collectively, our data support a novel septin-based mechanism for resealing damaged cells, in which the septin cytoskeleton plays a key structural role in remodeling the plasma membrane by promoting the formation of SEPT/F-actin/myosin IIA/ANXA2/S100A11 repair domains.
Assuntos
Actinas , Anexina A2 , Membrana Celular , Citoesqueleto , Septinas , Septinas/metabolismo , Septinas/genética , Humanos , Anexina A2/metabolismo , Anexina A2/genética , Membrana Celular/metabolismo , Citoesqueleto/metabolismo , Actinas/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Miosina não Muscular Tipo IIA/genética , Células HeLa , Cálcio/metabolismo , Proteínas S100/metabolismo , Proteínas S100/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genéticaRESUMO
ABSTRACT: Primary mucosal malignant melanoma of the nasal cavity is a rare tumor with aggressive behavior and a dismal prognosis. An extremely rare tumor that accounts for 0.7% to 1% of all melanomas in Caucasian populations and between 4% and 8% of malignant tumors of the nasal cavity and paranasal sinuses. Taking into account the rarity, it is important to note that malignant melanoma should be considered when making a differential diagnosis of tumors of the nose and paranasal sinuses. Two cases of primary malignant melanoma of the nasal cavity both arising in females, one in a 60-year-old and the other in a 64-year-old, both of whom presented with nasal obstruction and brief symptomatic epistaxis are being presented here. The diagnosis being confirmed by a histopathological examination along with an immunohistochemical analysis by using S100 and HMB45.
Assuntos
Melanoma , Cavidade Nasal , Mucosa Nasal , Neoplasias Nasais , Humanos , Melanoma/diagnóstico , Melanoma/patologia , Pessoa de Meia-Idade , Feminino , Cavidade Nasal/patologia , Neoplasias Nasais/patologia , Neoplasias Nasais/diagnóstico , Mucosa Nasal/patologia , Proteínas S100/metabolismoRESUMO
Acne vulgaris, rosacea, and hidradenitis suppurativa are enduring inflammatory skin conditions that frequently manifest with akin clinical attributes, posing a considerable challenge for their distinctive diagnosis. While these conditions do exhibit certain resemblances, they also demonstrate distinct underlying pathophysiological mechanisms and treatment modalities. Delving into both the molecular parallels and disparities among these three disorders can yield invaluable insights for refined diagnostics, effective management, and targeted therapeutic interventions. In this report, we present a comparative analysis of transcriptomic data across these three diseases, elucidating differentially expressed genes and enriched pathways specific to each ailment, as well as those shared among them. Specifically, we identified multiple zinc-binding proteins (SERPINA1, S100A7, S100A8, S100A9 and KRT16) as consistently highly upregulated genes across all three diseases. Our hypothesis suggests that these proteins could bind and sequester zinc, potentially leading to localized zinc deficiency and heightened inflammation. We identified high-dose dietary zinc as a promising therapeutic approach and confirmed its effectiveness through validation in an acne mouse model.
Assuntos
Acne Vulgar , Perfilação da Expressão Gênica , Hidradenite Supurativa , Rosácea , Zinco , Acne Vulgar/tratamento farmacológico , Acne Vulgar/genética , Zinco/uso terapêutico , Zinco/metabolismo , Rosácea/tratamento farmacológico , Rosácea/genética , Hidradenite Supurativa/tratamento farmacológico , Hidradenite Supurativa/genética , Animais , Camundongos , Humanos , Proteína A7 Ligante de Cálcio S100/metabolismo , Proteína A7 Ligante de Cálcio S100/genética , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Transcriptoma , Proteínas S100/genética , Proteínas S100/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Regulação para CimaRESUMO
Tumor-derived exosomes bind to organ resident cells, activating S100 molecules during the remodeling of the local immune microenvironment. However, little is known regarding how organ resident cell S100A10 mediates cancer metastatic progression. Here, we provided evidence that S100A10 plays an important role in regulating the lung immune microenvironment and cancer metastasis. S100A10-deficient mice reduced cancer metastasis in the lung. Furthermore, the activation of S100A10 within lung fibroblasts via tumor-derived exosomes increased the expression of CXCL1 and CXCL8 chemokines, accompanied by the myeloid-derived suppressor cells (MDSCs) recruitment. S100A10 inhibitors such as 1-Substituted-4-Aroyl-3-hydroxy-5-Phenyl-1 H-5-pyrrol-2(5 H)-ones inhibit lung metastasis in vivo. Our findings highlight the crucial role of S100A10 in driving MDSC recruitment in order to remodel the lung immune microenvironment and provide potential therapeutic targets to block cancer metastasis to the lung.
Assuntos
Neoplasias Pulmonares , Células Supressoras Mieloides , Proteínas S100 , Microambiente Tumoral , Animais , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Camundongos , Microambiente Tumoral/imunologia , Proteínas S100/metabolismo , Proteínas S100/genética , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Humanos , Camundongos Knockout , Exossomos/metabolismoRESUMO
BACKGROUND: Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. RESULTS: At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. CONCLUSION: Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.
Assuntos
Abatacepte , Antirreumáticos , Artrite Juvenil , Biomarcadores , Humanos , Abatacepte/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/sangue , Masculino , Feminino , Criança , Biomarcadores/sangue , Antirreumáticos/uso terapêutico , Calgranulina B/sangue , Adolescente , Resultado do Tratamento , Pré-Escolar , Calgranulina A/sangue , Proteína S100A12/sangue , Proteínas S100/sangueRESUMO
It is now understood that identical gene fusions may be shared by different entities. We report a distinctive neoplasm of the skin and subcutis, harboring the Ewing sarcoma-associated EWSR1::FLI1 fusion but differing otherwise from Ewing sarcoma. Slides and blocks for 5 cutaneous neoplasms coded as other than Ewing sarcoma and harboring EWSR1::FLI1 were retrieved. Immunohistochemical and molecular genetic results were abstracted from reports. Methylation profiling was performed. Clinical information was obtained. The tumors occurred in 4 men and 1 woman (median: 25 years of age; range: 19-69 years) and involved the skin/subcutis of the back (2), thigh, buttock, and chest wall (median: 2.4 cm; range: 1-11 cm). Two tumors were present "years" before coming to clinical attention. The lesions were multinodular and circumscribed and consisted of nests of bland, round cells admixed with hyalinized collagenous bands containing spindled cells. Hemorrhage and cystic change were often present; necrosis was absent. All were diffusely S100 protein/SOX10-positive; 4 of 5 were CD99-negative. One tested case was strongly positive for NKX2.2. A variety of other tested markers were either focally positive (glial fibrillary acidic protein, p63) or negative. Molecular genetic results were as follows: EWSR1 exon 7::FLI1 exon 8, EWSR1 exon 11::FLI1 exon 5, EWSR1 exon 11::FLI1 exon 6, EWSR1 exon 7::FLI1 exon 6, and EWSR1 exon 10::FLI1 exon 6. Methylation profiling (3 cases) showed these to form a unique cluster, distinct from Ewing sarcoma. All patients underwent excision with negative margins; one received 1 cycle of chemotherapy. Clinical follow-up showed all patients to be alive without disease (median: 17 months; range: 11-62 months). Despite similar gene fusions, the morphologic, immunohistochemical, epigenetic, and clinical features of these unique EWSR1::FLI1-fused neoplasms of the skin and subcutis differ substantially from Ewing sarcoma. Interestingly, EWSR1 rearrangements involved exons 10 or 11, only rarely seen in Ewing sarcoma, in a majority of cases. Superficial neurocristic EWSR1::FLI1 fusion tumors should be rigorously distinguished from true cutaneous Ewing sarcomas.