RESUMEN
Over the past 20 years, increasing evidence has demonstrated that immunoglobulins (Igs) can be widely generated from non B cells, including normal and malignant mammary epithelial cells. In normal breast tissue, the expression of IgG and IgA has been identified in epithelial cells of mammary glands during pregnancy and lactation, which can be secreted into milk, and might participate in neonatal immunity. On the other hand, non B-IgG is highly expressed in breast cancer cells, correlating with the poor prognosis of patients with breast cancer. Importantly, a specific group of IgG, bearing a unique N-linked glycan on the Asn162 site and aberrant sialylation modification at the end of the novel glycan (referred to as sialylated IgG (SIA-IgG)), has been found in breast cancer stem/progenitor-like cells. SIA-IgG can significantly promote the capacity of migration, invasiveness, and metastasis, as well as enhance self-renewal and tumorigenicity in vitro and in vivo. These findings suggest that breast epithelial cells can produce Igs with different biological activities under physiological and pathological conditions. During lactation, these Igs could be the main source of milk Igs to protect newborns from pathogenic infections, while under pathological conditions, they display oncogenic activity and promote the occurrence and progression of breast cancer.
Asunto(s)
Neoplasias de la Mama , Células Epiteliales , Glándulas Mamarias Humanas , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/inmunología , Células Epiteliales/metabolismo , Animales , Glándulas Mamarias Humanas/metabolismo , Glándulas Mamarias Humanas/patología , Lactancia/metabolismo , Embarazo , Inmunoglobulina G/metabolismo , Inmunoglobulina G/inmunología , Inmunoglobulinas/metabolismoRESUMEN
Lung squamous cell carcinoma (LUSC) kills more than four million people yearly. Creating more trustworthy tumor molecular markers for LUSC early detection, diagnosis, prognosis, and customized treatment is essential. Cuproptosis, a novel form of cell death, opened up a new field of study for searching for trustworthy tumor indicators. Our goal was to build a risk model to assess drug sensitivity, monitor immune function, and predict prognosis in LUSC patients. The 19 cuproptosis-related genes were found in the literature, and patient genomic and clinical information was collected using the Cancer Genomic Atlas (TCGA) database. The LUSC patients were grouped using unsupervised clustering techniques, and 7626 differentially expressed genes were identified. Using univariate COX analysis, LASSO regression analysis, and multivariate COX analysis, a prognostic model for LUSC patients was developed. The tumor immune escape was evaluated using the Tumor Immune Dysfunction and Exclusion (TIDE) method. The R packages 'pRRophetic,' 'ggpubr,' and 'ggplot2' were utilized to examine drug sensitivity. For modeling, a 6-cuproptosis-based gene signature was found. Patients with high-risk LUSC had significantly worse survival rates than those with low-risk conditions. The possibility of tumor immunological escape was increased in patients with higher risk scores due to more immune cell inactivation. For patients with high-risk LUSC, we discovered seven potent potential drugs (AZD6482, CHIR.99021, CMK, Embelin, FTI.277, Imatinib, and Pazopanib). In conclusion, the cuproptosis-based genes predictive risk model can be utilized to predict outcomes, track immune function, and evaluate medication sensitivity in LUSC patients.
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Although effective, immune checkpoint blockade induces response in only a subset of cancer patients. There is an urgent need to discover new immune checkpoint targets. Recently, it was found that a class of sialic acid-binding immunoglobulin-like lectins (Siglecs) expressed on the surface of T cells in cancer patients inhibit T cell activation through their intracellular immunosuppressive motifs by recognizing sialic acid-carrying glycans, sialoglycans. However, ligands of Siglecs remain elusive. Here, we report sialylated IgG (SIA-IgG), a ligand to Siglec-7, that is highly expressed in epithelial cancer cells. SIA-IgG binds Siglec-7 directly and inhibits TCR signals. Blocking of either SIA-IgG or Siglec-7 elicited potent antitumor immunity in T cells. Our study suggests that blocking of Siglec-7/SIA-IgG offers an opportunity to enhance immune function while simultaneously sensitizing cancer cells to immune attack.
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Ácido N-Acetilneuramínico , Neoplasias , Humanos , Ácido N-Acetilneuramínico/metabolismo , Linfocitos T/metabolismo , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Polisacáridos , Inmunoglobulina GRESUMEN
CCDC134 (coiled-coil domain containing 134), a cytokine-like molecule, was previously reported to exert antitumor effects by augmenting CD8+ T-cell mediated immunity. However, the dynamic changes in CCDC134 expression patterns in the spinal cord that may be involved in the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, remains unclear. In this study, we found that CCDC134 expression was markedly increased in the spinal cord during the progression of EAE. Furthermore, we demonstrated that CCDC134 significantly reduced the severity and slowed the progression of EAE, which correlated with reduced spinal cord inflammation and demyelination. The underlying mechanism of CCDC134-induced effects involved inhibition of T helper (Th)-1 and Th17 cell differentiation and secretion of its key effector molecules IFN-γ and IL-17A via regulation of JAK/STAT signaling. These findings indicate that CCDC134 exerts potent anti-inflammatory effects through the selective modulation of pathogenic Th1 and Th17 cells by targeting critical signaling pathways. The study provides insights into the role of CCDC134 as a unique therapeutic agent for the treatment of autoimmune diseases.
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Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Proteínas de la Membrana/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/metabolismo , Transducción de Señal/efectos de los fármacos , Médula Espinal/metabolismo , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/fisiología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/fisiologíaRESUMEN
CCDC134 might be an immune cytokine and plays important and complex roles in the process in vivo. It was proved to illustrate its potent antitumor effects by augmenting CD8+ T-cell-mediated immunity, but its role in the development of rheumatoid arthritis (RA) remains unclear. In this study, we demonstrated that development of adjuvant-induced arthritis and pro-inflammatory responses were more ameliorated in CCDC134-overexpressing transgenic mice than those in WT mice. The underlying mechanism of CCDC134-induced effects involved inhibition of T helper (Th) 1 and Th17 cell differentiation. These findings indicate that overexpression of CCDC134 exerts potent anti-inflammatory effects through selective modulation of pathogenic Th1 and Th17 cells, and might provide insights into the role of CCDC134 as a unique therapeutic agent for the treatment of rheumatoid arthritis.
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Artritis Experimental/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Animales , Artritis Experimental/patología , Proteínas de la Membrana/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
AIMS: Cancer cell-derived immunoglobulin (Ig)G (cancer-IgG) has been found to be involved in the pathogenesis and progression of many cancers, including lung cancer. The aim of the present study was to investigate the relationship between cancer-IgG expression in lung adenocarcinoma (ADC) and clinicopathological characteristics and clinical outcome. METHODS AND RESULTS: Immunohistochemical analysis was performed using an RP215 monoclonal antibody to determine cancer-IgG expression in 140 lung ADC patients. Cell migration and invasion were analysed in A549 cell line after short interfering RNA (siRNA) knockdown of IgG and cell sorting by flow cytometry. Our results show that RP215 immunostaining score is correlated significantly with local invasion (P < 0.05) and tumour differentiation (P < 0.05) in ADC. Moreover, RP215 staining was significantly higher in metastatic tumours than in primary tumours (P < 0.0001). The knockdown of IgG resulted in a reduction of cell migration and invasion. In contrast, RP215-positive cells displayed greater migration and invasion ability than RP215-negative cells. Additionally, a higher RP215 immunostaining score was associated significantly with poor prognosis. CONCLUSIONS: RP215 staining is correlated strongly with differentiation, local invasion, metastasis and clinical outcome of patients with lung ADC. Our results suggest that RP215 can serve as a biomarker for prognosis of lung ADC.
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Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Biomarcadores de Tumor/análisis , Inmunoglobulina G/biosíntesis , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Adenocarcinoma/mortalidad , Adenocarcinoma del Pulmón , Anticuerpos Monoclonales , Western Blotting , Citometría de Flujo , Humanos , Cadenas Pesadas de Inmunoglobulina/análisis , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , ARN Interferente Pequeño , Análisis de Matrices Tisulares , TransfecciónRESUMEN
The innate immune system of the skin is thought to depend largely on a multi-layered mechanical barrier supplemented by epidermis-derived antimicrobial peptides. To date, there are no reports of antimicrobial antibody secretion by the epidermis. In this study, we report the expression of functional immunoglobulin G (IgG) and immunoglobulin A (IgA), previously thought to be only produced by B cells, in normal human epidermal cells and the human keratinocyte line HaCaT. While B cells express a fully diverse Ig, epidermal cell-expressed IgG or IgA showed one or two conservative VHDJH rearrangements in each individual. These unique VDJ rearrangements in epidermal cells were found neither in the B cell-derived Ig VDJ databases published by others nor in our positive controls. IgG and IgA from epidermal cells of the same individual had different VDJ rearrangement patterns. IgG was found primarily in prickle cells, and IgA was mainly detected in basal cells. Both epidermal cell-derived IgG and IgA showed potential antibody activity by binding pathogens like Staphylococcus aureus, the most common pathogenic skin bacteria, but the microbial-binding profile was different. Our data indicates that normal human epidermal cells spontaneously express IgG and IgA, and we speculate that these Igs participate in skin innate immunity.
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Epidermis/metabolismo , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Línea Celular , Bases de Datos Factuales , Epidermis/patología , Humanos , Inmunoglobulina A/genética , Inmunoglobulina A/metabolismo , Inmunoglobulina G/genética , Inmunoglobulina G/metabolismo , Inmunohistoquímica , Queratinocitos/citología , Queratinocitos/metabolismo , Microscopía Confocal , Staphylococcus aureus/inmunología , Transcripción Genética , Recombinación V(D)JRESUMEN
Lung squamous cell carcinoma has so far lacked effective targets for diagnosis and treatment. In cancer research, long noncoding RNAs (LncRNAs) emerge as novel therapeutic targets and biomarkers. Cuprophosis is a new death type involving multiple biological processes in tumor cells. Here, we aimed to explore whether Cuprophosis-related lncRNAs could be used to predict prognosis, assess immune function, and test drug sensitivity in LUSC patients. The Cancer Genome Map (TCGA) was used to obtain genome and clinical data, and Cuprophosis-relevant genes were found in the literature. A cuproptosis-related lncRNA risk model was built using co-expression analysis, univariate/multivariate Cox regression, and LASSO analysis. The survival analysis was used to assess the model's prognostic value. The univariate and multivariate Cox regression analyses were performed to determine whether risk score, age, gender, or clinical stages could be used as independent prognostic factors. Gene Set Enrichment Analysis and mutation analysis were performed on differentially expressed mRNA between high-risk and low-risk groups. The (TIDE) algorithm was used to conduct immunological functional analysis and drug sensitivity testing. Five cuproptosis-related LncRNAs were identified, and the selected LncRNAs constructed a prognosis model. According to the Kaplan-Meier survival analysis, the overall survival time for patients in the high-risk group was shorter than for those in the low-risk group. For LUSC patients, the risk score serves as an independent prognostic indicator. The GO and KEGG enrichment analysis revealed that the differentially expressed mRNAs between the high- and low-risk groups were enriched in several immune-related processes. The enrichment score of differentially expressed mRNAs in the high-risk group is higher than that of the low-risk group in multiple immune function pathways, including the IFN-γ and MHC I pathways. The Tumor Immune Dysfunction and Exclusion (TIDE) test revealed that the high-risk group was more likely to experience immune escape. The drug sensitivity analysis showed that patients with low-risk ratings were likely to respond to GW441756 and Salubrinal. In contrast, patients with higher risk scores were more responsive to dasatinib and Z-LLNIe CHO. The 5-Cuprophosis-related lncRNA signature can be used to predict prognosis, assess immune function, and test drug sensitivity in LUSC patients.
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Human transcriptional adaptor hADA2a is an important component of the general control nonderepressible 5 (GCN5) histone acetyltransferase complex. Here, we report that coiled-coil domain containing 134 (CCDC134), a novel nuclear protein, binds to hADA2a and enhances the stability of the hADA2a protein in unstressed conditions. Furthermore, CCDC134 was found to participate in the p300/CBP-associated factor (PCAF) complex via hADA2a and affect the histone acetyltransferase activity of the complex. We also found that CCDC134 increased the PCAF-dependent K320 acetylation of p53 and p53 protein stability in the presence of hADA2a overexpression. Moreover, we demonstrated the biological significance of the interaction between CCDC134 and hADA2a. CCDC134 showed obvious nuclear accumulation after ultraviolet (UV) irradiation, and the knockdown of endogenous CCDC134 suppressed hADA2a-induced cell apoptosis activity and G1/S cell cycle arrest. Together, our findings indicate that CCDC134 might act as a novel regulator of hADA2a, and plays roles in the PCAF complex via hADA2a to affect its acetyltransferase activity and UV-induced DNA damage repair.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Apoptosis , Puntos de Control del Ciclo Celular/fisiología , Daño del ADN , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Acetiltransferasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteínas de Unión al ADN , Células HEK293 , Humanos , Proteínas de la Membrana , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Background: Osteosarcoma is a malignant bone tumor that typically occurs in adolescents or children under 20 years of age. Developing efficient clinical prognostic markers is crucial for improving the treatment of osteosarcoma patients. Methods: Three datasets related to osteosarcoma were acquired from the Gene Expression Omnibus (GEO) database. A gene signature model was established using the Limma package in the R software, univariate and multivariate survival analyses, and least absolute shrinkage and selection operator (LASSO) algorithms. The gene signature was then verified using external datasets. Results: From the GEO database, 242 differentially expressed genes were identified. A total of 590 unique genes, including 380 genes from the human protein interaction network, were found to be related to biological processes such as bone development and bone cell development. Univariate Cox survival analyses revealed 43 genes that were associated with the prognosis of osteosarcoma patients. A seven-gene signature [retinitis pigmentosa 2 (RP2), polyhydroxybutyrate (PHB), myosin VI (MYO6), mutL homolog 1 (MLH1), Casein kinase 2 beta (CSNK2B), ribosomal protein L37A (RPL37A), and CCAAT/enhancer binding protein alpha (CEBPA)] was developed using LASSO regression analysis and multivariate regression analysis. This gene signature could stratify the prognostic risk of sample cases in the training set, the test set, and the external verification set (P<0.01). The area under the receiver operating characteristic curve for the 5-year survival was higher than 0.72 in both the training and verification groups. Conclusions: In this study, a seven-gene signature was developed that is highly efficient at predicting the prognosis of patients with osteosarcoma, and therefore, this signature may be a crucial guide in the treatment of these patients.
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The incidence rate of breast cancer is the highest in the world, and major problem in the clinical treatment is the therapy resistance of breast cancer stem cells (CSCs). Thus, new therapeutic approaches targeting breast CSCs are needed. Our previous study demonstrated cancer-derived sialylated IgG (SIA-IgG) is highly expressed in cancer cells with stem/progenitor features. Furthermore, a high frequency of SIA-IgG in breast cancer tissue predicted metastasis and correlated with poor prognosis factors, and depletion of IgG in breast cancer leads to lower malignancy of cancer cells, suggesting SIA-IgG could be a potential therapeutic target in breast cancer. In this study, we first investigated the relationship of SIA-IgG expression with the clinicopathological characteristics and clinical prognosis of breast carcinoma patients, and the data confirmed that the expression of SIA-IgG confers poor prognosis in breast cancer. Successively, by using a monoclonal antibody specifically against SIA-IgG, we targeted SIA-IgG on the surface of MDA-MB-231 cells and detected their functional changes, and the results suggested SIA-IgG to be a promising antibody therapeutic target in breast cancer. In addition, we explored the mechanism of action at the molecular level of SIA-IgG on breast cancer cell, the findings suggest that SIA-IgG promotes proliferation, metastasis, and invasion of breast cancer cells through the Wnt/ß-catenin signaling pathway. Developing therapeutic antibody needs effective therapeutic target, and the antibody should better be a monoclonal antibody with high affinity and high specificity. This study provides a potential prognostic marker and a novel therapeutic target for breast cancer.
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Neoplasias de la Mama , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Inmunoglobulina G , Pronóstico , Vía de Señalización WntRESUMEN
Coiled-coil domain containing 134 (CCDC134) has been shown to serve as an immune cytokine to exert antitumor effects and to act as a novel regulator of hADA2a to affect PCAF acetyltransferase activity. While Ccdc134 loss causes abnormal brain development in mice, the significance of CCDC134 in neuronal development in vivo is controversial. Here, we report that CCDC134 is highly expressed in Purkinje cells (PCs) at all developmental stages and regulates mammalian cerebellar development in a cell type-specific manner. Selective deletion of Ccdc134 in mouse neural stem cells (NSCs) caused defects in cerebellar morphogenesis, including a decrease in the number of PCs and impairment of PC dendritic growth, as well as abnormal granule cell development. Moreover, loss of Ccdc134 caused progressive motor dysfunction with deficits in motor coordination and motor learning. Finally, Ccdc134 deficiency inhibited Wnt signaling but increased Ataxin1 levels. Our findings provide evidence that CCDC134 plays an important role in cerebellar development, possibly through regulating Wnt signaling and Ataxin1 expression levels, and in controlling cerebellar function for motor coordination and motor learning, ultimately making it a potential contributor to cerebellar pathogenesis.
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Cerebelo/metabolismo , Proteínas de la Membrana/genética , Actividad Motora/fisiología , Células-Madre Neurales/metabolismo , Células de Purkinje/metabolismo , Animales , Proliferación Celular/fisiología , Regulación del Desarrollo de la Expresión Génica/genética , Ratones Noqueados , Neurogénesis/fisiología , Neuronas/metabolismoRESUMEN
BACKGROUND: An increasing number of studies have indicated that the abnormal expression of certain long noncoding RNAs (lncRNAs) is linked to the overall survival (OS) of patients with myeloma. METHODS: Gene expression data of myeloma patients were downloaded from the Gene Expression Omnibus (GEO) database (GSE4581 and GSE57317). Cox regression analysis, Kaplan-Meier, and receiver operating characteristic (ROC) analysis were performed to construct and validate the prediction model. Single sample gene set enrichment (ssGSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to predict the function of a specified lncRNA. RESULTS: In this study, a seven-lncRNA signature was identified and used to construct a risk score system for myeloma prognosis. This system was used to stratify patients with different survival rates in the training set into high-risk and low-risk groups. Test set, the entire test set, the external validation set, and the myeloma subtype achieved the authentication of the results. In addition, functional enrichment analysis indicated that 7 prognostic lncRNAs may be involved in the tumorigenesis of myeloma through cancer-related pathways and biological processes. The results of the immune score showed that IF_I was negatively correlated with the risk score. Compared with the published gene signature, the 7-lncRNA model has a higher C-index (above 0.8). CONCLUSION: In summary, our data provide evidence that seven lncRNAs could be used as independent biomarkers to predict the prognosis of myeloma, which also indicated that these 7 lncRNAs may be involved in the progression of myeloma.
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Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , ARN Largo no Codificante/genética , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Mieloma Múltiple/inmunología , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Autoimmune diabetes is a disorder of immune homeostasis that leads to targeted insulin-secreting islet ß cell destruction characterized by insulitis. Human amylin (hA) is an important neuroendocrine hormone co-secreted with insulin by pancreatic ß cells. Here, we report hA immune-modulatory action through inducing regulatory T cells. We ex vivo-treated human peripheral blood mononuclear cells (hPBMCs) with hA for 24 h and counted CD4+Foxp3+ regulatory T cells (Treg) using flow cytometry. Diabetic status was monitored and splenic Treg were measured in non-obese diabetic (NOD) male mice. NOD mice were intraperitoneally injected once daily with hA (n = 25) or solvent for control (n = 25) for 7 months continuously. Spleen tissues were collected at the end of intervention and processed for flow cytometry and Western blot. We found a 2.9-fold (p < 0.05) increase of CD4+Foxp3+ Treg in hPBMCs treated with 10 nmol/L hA compared with negative control. Incidence of diabetes in hA-treated NOD mice decreased 44% (p = 0.045) in the 6th month and 57% (p = 0.0002) in the 7th month. Meanwhile, the hA treatment induced a 1.5-fold increase of CD4+Foxp3+ Treg from mouse splenocytes (p = 0.0013). Expression of transforming growth factor-ß (TGF-ß) and toll-like receptor-4 (TLR-4) were upregulated in hA-treated mice. Human amylin might protect against autoimmune diabetes via the induction of CD4+Foxp3+ Treg, which suggests a novel approach to improve autoimmune conditions.
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Diabetes Mellitus Tipo 1/inmunología , Células Secretoras de Insulina/patología , Polipéptido Amiloide de los Islotes Pancreáticos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos CD4/metabolismo , Células Cultivadas , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunomodulación , Masculino , Ratones , Ratones Endogámicos NOD , Receptor Toll-Like 4/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
It is increasingly recognized that many human carcinomas express immunoglobulin (Ig) molecules that are distinct from B-cell-derived Ig and play important roles in cancer initiation, progression, and metastasis. However, the molecular mechanisms underlying the functions of cancer-derived Ig remain elusive. Here, we report that lung squamous cell carcinoma (LSCC) cells frequently express high levels of cancer IgG (CIgG) that is specifically recognized by a monoclonal antibody RP215. RP215 recognizes CIgG via a novel epitope that involves an N-glycan modification at a non-consensus site within the CH1 domain. We demonstrate that RP215 recognized CIgG (RP215-CIgG) promotes survival, migration and in vivo growth of LSCC cells, and these oncogenic activities are strongly inhibited by RP215. Mechanistically, RP215-CIgG executes its oncogenic function through interacting with the integrin α6ß4 complex and activating the FAK and Src pathways. Notably, the CIgG-integrin-FAK signaling depends on the N-glycan epitope, which is inhibited by RP215. Together, our studies identified a novel CIgG molecule that activates the oncogenic integrin-FAK signaling in LSCC cells. In addition, the activity of CIgG is inhibited by RP215, providing an attractive target for antibody-based therapy of LSCC.
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Anticuerpos Monoclonales/farmacología , Antineoplásicos Inmunológicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Inmunoglobulina G/metabolismo , Neoplasias Pulmonares/patología , Animales , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia sin Enfermedad , Epítopos/inmunología , Femenino , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Inmunoglobulina G/inmunología , Integrina alfa6beta4/metabolismo , Pulmón/patología , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Ratones SCID , Persona de Mediana Edad , Pronóstico , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Currently, natural IgM antibodies are considered to be the constitutively secreted products of B-1 cells in mice and humans. In this study, we found that mouse epithelial cells, including liver epithelial cells and small intestinal epithelial cells (IECs), could express IgM that also showed natural antibody activity. Moreover, similar to the B-1 cell-derived natural IgM that can be upregulated by TLR9 agonists (mimicking bacterial infection), the expression of epithelial cell-derived natural IgM could also be significantly increased by TLR9 signaling. More importantly, the epithelial cell-derived IgM was polyreactive, and it could recognize single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), lipopolysaccharide (LPS), and insulin with low affinity; additionally, TLR9 agonists could enhance it in a MyD88-dependent manner. Furthermore, epithelial cell-derived IgM could bind various bacteria; therefore, it could be involved in anti-infection responses. Together, these results highlight the fact that epithelial cells are an important source of natural IgM, in addition to that produced by B-1 cells, and IgM contributes to the innate immune responses in local tissues, further demonstrating that the epithelium is a first line of defense in the protection against invading microbes.
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Células Epiteliales/metabolismo , Inmunidad Innata/fisiología , Inmunoglobulina M/metabolismo , Animales , Linfocitos B/metabolismo , Bacterias/inmunología , Células Cultivadas , ADN de Cadena Simple/inmunología , Citometría de Flujo , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Mutantes , Transducción de Señal/fisiología , Receptor Toll-Like 9/antagonistas & inhibidoresRESUMEN
High expression of immunoglobulin G (IgG) in many non-B cell malignancies and its non-conventional roles in promoting proliferation and survival of cancer cells have been demonstrated. However, the precise function of non-B IgG remains incompletely understood. Here we define the antigen specificity of RP215, a monoclonal antibody that specifically recognizes the IgG in cancer cells. Using RP215, our study shows that IgG is overexpressed in cancer cells of epithelial lineage, especially cells with cancer stem/progenitor cell-like features. The RP215-recognized IgG is primarily localized on the cell surface, particularly lamellipodia-like structures. Cells with high IgG display higher migration, increased invasiveness and metastasis, and enhanced self-renewal and tumorgenecity ability in vitro and in vivo. Importantly, depletion of IgG in breast cancer leads to reduced adhesion, invasion and self-renewal and increased apoptosis of cancer cells. We conclude that high expression of IgG is a novel biomarker of tumor progression, metastasis and cancer stem cell maintenance and demonstrate the potential therapeutic benefits of RP215-recognized IgG targeted strategy.
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Neoplasias de la Mama/inmunología , Células Epiteliales/inmunología , Inmunoglobulina G/inmunología , Células Madre Neoplásicas/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Western Blotting , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Movimiento Celular/inmunología , Proliferación Celular/genética , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Expresión Génica/inmunología , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/genética , Inmunohistoquímica , Células MCF-7 , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/inmunología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/inmunología , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Metástasis de la Neoplasia , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trasplante HeterólogoRESUMEN
CCDC134 is a poorly characterized secreted protein that may act as an immune cytokine. Here, we show that CCDC134 is differentially expressed on resting and activated immune cells and that it promotes CD8(+) T-cell activation, proliferation, and cytotoxicity by augmenting expression of the T-cell effector molecules IFNγ, TNFα, granzyme B, and perforin. CCDC134 facilitated infiltration of CD8(+) T cells with enhanced cytolytic activity into tumors, demonstrating strong antitumor effects in a CD8(+) T-cell-dependent manner. Mechanistically, in CD8(+) T cells, exposure to CCDC134 promoted cell proliferation through the JAK3-STAT5 pathway, a classic feature of many cytokines of the common γ-chain (γ(c)) cytokine receptor family. Overall, our results provide evidence that CCDC134 may serve as a member of the γ(c) cytokine family and illustrate its potent antitumor effects by augmenting CD8(+) T-cell-mediated immunity.
Asunto(s)
Inmunoterapia , Melanoma Experimental/inmunología , Proteínas de la Membrana/fisiología , Linfocitos T Citotóxicos/inmunología , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Citotoxicidad Inmunológica , Femenino , Interferón gamma/metabolismo , Activación de Linfocitos , Melanoma Experimental/metabolismo , Melanoma Experimental/terapia , Proteínas de la Membrana/farmacología , Ratones Endogámicos C57BL , Ratones SCID , Ratones Transgénicos , Linfocitos T Citotóxicos/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
It is well known that B-1 B cells are the main cell type that is responsible for the production of natural immunoglobulin M (IgM) and can respond to infection by increasing IgM secretion. However, we unexpectedly found that some epithelial cells also can express rearranged IgM transcript that has natural IgM characteristics, such as germline-encoded and restricted rearrangement patterns. Here we studied IgM expression in human non-B cells and found that IgM was frequently expressed by many human epithelial cancer cells as well as non-cancer epithelial cells. Moreover, CD79A and CD79B, two molecules that are physically linked to membranous IgM on the surface of B cells to form the B cell antigen receptor complex, were also expressed on the cell surface of epithelial cancer cells and co-located with IgM. Like the natural IgM, the epithelial cancer cell-derived IgM recognized a series of microbial antigens, such as single-stranded DNA, double-stranded DNA, lipopolysaccharide, and the HEp-2 cell antigen. More important, stimulation of the toll-like receptor 9 (TLR9), which mimics bacterial infection, substantially increased the secretion of IgM in human epithelial cancer cells. These findings indicate that human epithelial cancer cells as well as non-cancer epithelial cells can spontaneously produce IgM with natural antibody activity.