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Intestinal dysmotility syndromes have been epidemiologically associated with several antecedent bacterial and viral infections. To model this phenotype, we previously infected mice with the neurotropic flavivirus, West Nile Virus (WNV) and demonstrated intestinal transit defects. Here, we find that within one week of WNV infection, enteric neurons and glia become damaged, resulting in sustained reductions of neuronal cells and their networks of connecting fibers. Using cell-depleting antibodies, adoptive transfer experiments, and mice lacking specific immune cells or immune functions, we show that infiltrating WNV-specific CD4+ and CD8+ T cells damage the enteric nervous system (ENS) and glia, which leads to intestinal dysmotility; these T cells use multiple and redundant effector functions including perforin and Fas ligand. In comparison, WNV-triggered ENS injury and intestinal dysmotility appears to not require infiltrating monocytes and damage may be limited by resident muscularis macrophages. Overall, our experiments support a model whereby antigen specific T cell subsets and their effector molecules responding to WNV infection direct immune pathology against enteric neurons and supporting glia that results in intestinal dysmotility.
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Ischemic stroke-induced neuronal cell death leads to the permanent impairment of brain function. The Fas-mediating extrinsic apoptosis pathway and the cytochrome c-mediating intrinsic apoptosis pathway are two major molecular mechanisms contributing to neuronal injury in ischemic stroke. In this study, we employed a Fas-blocking peptide (FBP) coupled with a positively charged nona-arginine peptide (9R) to form a complex with negatively charged siRNA targeting Bax (FBP9R/siBax). This complex is specifically designed to deliver siRNA to Fas-expressing ischemic brain cells. This complex enables the targeted inhibition of Fas-mediating extrinsic apoptosis pathways and cytochrome c-mediating intrinsic apoptosis pathways. Specifically, the FBP targets the Fas/Fas ligand signaling, while siBax targets Bax involved in mitochondria disruption in the intrinsic pathway. The FBP9R carrier system enables the delivery of functional siRNA to hypoxic cells expressing the Fas receptor on their surface-a finding validated through qPCR and confocal microscopy analyses. Through intranasal (IN) administration of FBP9R/siCy5 to middle cerebral artery occlusion (MCAO) ischemic rat models, brain imaging revealed the complex specifically localized to the Fas-expressing infarcted region but did not localize in the non-infarcted region of the brain. A single IN administration of FBP9R/siBax demonstrated a significant reduction in neuronal cell death by effectively inhibiting Fas signaling and preventing the release of cytochrome c. The targeted delivery of FBP9R/siBax represents a promising alternative strategy for the treatment of brain ischemia.
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Apoptosis plays a crucial role in neuronal injury, with substantial evidence implicating Fas-mediated cell death as a key factor in ischemic strokes. To address this, inhibition of Fas-signaling has emerged as a promising strategy in preventing neuronal cell death and alleviating brain ischemia. However, the challenge of overcoming the blood-brain barrier (BBB) hampers the effective delivery of therapeutic drugs to the central nervous system (CNS). In this study, we employed a 30 amino acid-long leptin peptide to facilitate BBB penetration. By conjugating the leptin peptide with a Fas-blocking peptide (FBP) using polyethylene glycol (PEG), we achieved specific accumulation in the Fas-expressing infarction region of the brain following systemic administration. Notably, administration in leptin receptor-deficient db/db mice demonstrated that leptin facilitated the delivery of FBP peptide. We found that the systemic administration of leptin-PEG-FBP effectively inhibited Fas-mediated apoptosis in the ischemic region, resulting in a significant reduction of neuronal cell death, decreased infarct volumes, and accelerated recovery. Importantly, neither leptin nor PEG-FBP influenced apoptotic signaling in brain ischemia. Here, we demonstrate that the systemic delivery of leptin-PEG-FBP presents a promising and viable strategy for treating cerebral ischemic stroke. Our approach not only highlights the therapeutic potential but also emphasizes the importance of overcoming BBB challenges to advance treatments for neurological disorders.
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Isquemia Encefálica , Accidente Cerebrovascular , Animales , Ratones , Leptina/farmacología , Apoptosis , Isquemia Encefálica/tratamiento farmacológico , Muerte Celular , Péptidos/farmacologíaRESUMEN
BACKGROUND: Diabetic kidney disease is a major cause of global end-stage renal diseases. Ectopic lipid deposition in the renal tissues of diabetic kidney disease is one major factor leading to renal fibrosis and chronic kidney disease. Pterostilbene has been reported to display lipid-lowing activity and participate in many kidney diseases. However, the influence of pterostilbene on the ectopic lipid deposition is unclear. We intend to explore the influence of pterostilbene on the ectopic lipid deposition in the kidneys of mice induced by high fat. METHODS: A high-fat diet-induced diabetic mouse model was established to detect the alleviative effect of pterostilbene on the ectopic lipid deposition in the kidneys of diabetic mice. A biochemical analysis was performed to examine the levels of urine albumin, urine creatinine, serum creatinine, and blood urea nitrogen in mice after pterostilbene treatment. Histological analysis was conducted to detect the degree of renal injury and fibrosis. Oil red O staining and immunohistochemical staining were carried out to evaluate lipid droplets and the expression of adipose differentiation-related protein in renal tissues of the mice treated by pterostilbene. The protein levels were assessed by Western blotting. RESULTS: Pterostilbene inhibits the expression of the TGF-ß1 and p-smad3 and suppresses the protein levels of SREBP-1 and FAS, and it ultimately reduces the ectopic lipid deposition, alleviates the renal tubular damage and renal fibrosis in the kidneys of diabetic mice induced by high fat, and improves kidney function. CONCLUSION: Pterostilbene alleviates renal fibrosis and ectopic lipid deposition in the kidneys of diabetic mice induced by high-fat diet by inhibiting the TGF-ß1/smad3 signaling.
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Diabetes Mellitus Experimental , Nefropatías Diabéticas , Animales , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Dieta Alta en Grasa/efectos adversos , Fibrosis , Riñón/patología , Lípidos , Ratones , Resveratrol/metabolismo , Resveratrol/farmacología , Estilbenos , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Apoptosis genes Egr2, Fas and FasL are related to immune responses. However, the mechanism of these genes inducing apoptosis in fish are still not very clear. An acute hypoxia treatment (1.73 ± 0.06 mg/L) for 24 h was carried out on Japanese flounder (Paralichthys olivaceus). The increasingly dense apoptotic signals at 3 h, 6 h, 12 h by TUNEL in skeletal muscle indicated that hypoxia could quickly affect muscle growth and development. Furthermore, we concluded that the Egr2-FasL-Fas signal pathway, which was located at the upstream of apoptotic executor protein caspases, was related to the apoptosis by quantitative real-time PCR, protein concentration detection in ELISA and double gene in situ hybridization methods. The mechanism of the pathway was researched in transcription regulation and epigenetic modification by dual-luciferase reporter assay and bisulfite modified method, respectively. Egr2, as a transcription factor, could up-regulate the expression of FasL gene. And its binding site was mainly between -479 to -1 of FasL gene promoter. The 5th CpG dinucleotides (-514) methylation levels in FasL gene were significantly affected by hypoxia, and they were negatively correlated with its expressions. These suggested that the -514 site may be a very important site to regulate the FasL gene expression. Above results, we concluded that hypoxia activated the immune related signal pathway Egr2-FasL-Fas to induced skeletal muscle apoptosis to affect growth and development of Japanese flounder. The study revealed the mechanism of hypoxia induced apoptosis, which could provide a reference for fish immunity and aquaculture management.
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Lenguado , Animales , Apoptosis/fisiología , Proteína Ligando Fas/genética , Regulación de la Expresión Génica , Hipoxia/genética , Hipoxia/veterinaria , Transducción de SeñalRESUMEN
Obesity is a global public health issue. Obesity-related chronic low-grade inflammation (meta-inflammation) can lead to aberrant adipokine release and promote cardiometabolic diseases and obesity-related tumors. However, the mechanisms involved in the initiation of inflammatory responses in obesity and obesity-related tumors as well as metastasis are not fully understood. In this study, we found that the increased tumor necrosis factor-alpha (TNF-α) in adipocytes promoted the lung metastasis of MC38 colon cancer cells via Fas signaling. The release of TNF-α and interleukin (IL)-6 by Fas signaling in adipocytes was caused by the activation of the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways mediated by the interaction of Fas with Bmx, a non-receptor tyrosine kinase. Moreover, the Fas/Bmx complex is involved in the inflammation of adipocytes via Fas at the Tyr189 site and SH2 domain of Bmx. This is the first study to report the interaction between Fas and Bmx in adipocyte inflammation, which may provide clues for the development of potential new treatment strategies for obesity-related diseases.
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Neoplasias Colorrectales/genética , Neoplasias Pulmonares/genética , Obesidad/genética , Proteínas Tirosina Quinasas/genética , Receptor fas/genética , Adipocitos/metabolismo , Adipocitos/patología , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Humanos , Inflamación/genética , Inflamación/patología , Interleucina-6/genética , Neoplasias Pulmonares/secundario , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , FN-kappa B/genética , Metástasis de la Neoplasia , Obesidad/complicaciones , Obesidad/patología , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts, as well as continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, potentially novel flow cytometry strategies to quantify lung fibroblast subsets, and transcriptional profiling of lung fibroblasts by bulk and single cell RNA sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued profibrotic functions of lung fibroblasts. Our studies provide insights into the mechanisms that contribute to fibroblast survival, persistence, and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis impairs fibrosis resolution.
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Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Receptor fas/deficiencia , Animales , Bleomicina/toxicidad , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Fibroblastos/patología , Citometría de Flujo , Perfilación de la Expresión Génica , Homeostasis , Humanos , Fibrosis Pulmonar Idiopática/inducido químicamente , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , RNA-Seq , Transducción de Señal , Análisis de la Célula Individual , Receptor fas/genéticaRESUMEN
Heat stress (HS) causes significant economic losses in the poultry industry every year. However, the mechanisms for the adverse effects of HS on avian follicular development are largely unknown. The aim of this study was to test whether HS induces apoptosis of follicular cells and impairs egg production by activating the FasL/Fas and tumor necrosis factor (TNF)-α systems. To this end, Hy-Line Brown laying hens, at 32 wk of age, were either exposed to HS of 35°C to 37°C or maintained at 24°C to 26°C (control) for 5 D. At the end of the HS period, follicle numbers, apoptosis, FasL/Fas and TNF-α activation, oxidative stress, and hormone secretion were examined in ovarian follicles. Egg production was observed daily during both the stressed (day S1-S5) and the poststress recovery (day R1-R15) periods. The results demonstrated that HS on hens significantly 1) decreased laying rates from day S3 to R6; 2) reduced numbers of large yellow and hierarchical follicles; 3) triggered apoptosis while increasing the expression of FasL, Fas, TNF-α, and TNF-receptor 1 in small and large yellow follicles; and 4) increased levels of oxidative stress, corticotrophin-releasing hormone, and corticosterone while decreasing the estradiol/progesterone ratio in follicular fluid in small and large yellow follicles. Taken together, the results suggested that hen HS impaired egg production by reducing the number of follicles through inducing apoptosis and that it triggered apoptosis in follicular cells by activating the FasL/Fas and TNF-α systems.
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Apoptosis , Pollos , Proteína Ligando Fas , Respuesta al Choque Térmico , Neuropéptidos , Folículo Ovárico , Factor de Necrosis Tumoral alfa , Animales , Proteína Ligando Fas/genética , Femenino , Neuropéptidos/genética , Folículo Ovárico/citología , Ovulación/fisiología , Activación Transcripcional , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS. Although CD4+ T cells are implicated in MS pathogenesis and have been the main focus of MS research using the animal model experimental autoimmune encephalomyelitis (EAE), substantial evidence from patients with MS points to a role for CD8+ T cells in disease pathogenesis. We previously showed that an MHC class I-restricted epitope of myelin basic protein (MBP) is presented in the CNS during CD4+ T cell-initiated EAE. Here, we investigated whether naive MBP-specific CD8+ T cells recruited to the CNS during CD4+ T cell-initiated EAE engaged in determinant spreading and influenced disease. We found that the MBP-specific CD8+ T cells exacerbated brain but not spinal cord inflammation. We show that a higher frequency of monocytes and monocyte-derived cells presented the MHC class I-restricted MBP ligand in the brain compared with the spinal cord. Infiltration of MBP-specific CD8+ T cells enhanced ROS production in the brain only in these cell types and only when the MBP-specific CD8+ T cells expressed Fas ligand (FasL). These results suggest that myelin-specific CD8+ T cells may contribute to disease pathogenesis via a FasL-dependent mechanism that preferentially promotes lesion formation in the brain.
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Autoinmunidad/inmunología , Linfocitos T CD8-positivos/inmunología , Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/etiología , Vaina de Mielina/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Movimiento Celular , Encefalomielitis Autoinmune Experimental/inmunología , Proteína Ligando Fas/fisiología , Femenino , Masculino , Ratones , Ratones Endogámicos C3H , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Objective: To explore the selective effects of cyclamin on the proliferation and apoptosis of the liver cancer cells in vitro, and to clarify the molecular target and the underlying mechanisms. Methods: The human liver cancer HepG2 cells or normal human HL-7702 liver cells were divided into cyclamin groups (added with 0, 2 . 5, 5.0 and 10.0 jumol • L_ 1 cyclamin), cholesterol intervention group (cyclamin + 20.0 mg • L_ 1 cholesterol) and control group (0 . 5 % DMSO only). M T T assay was performed to determine the survival rates of cells in various groups. The cellular cholesterol level was measured by Filipin staining. Lactate dehydrogenase (L D H) release assay was used to determine the LDH realease levels in cells. Flow cytometry was used to detect the apoptotic rates of cells. The expressions of Fas, FADD and caspase-8 proteins were measured by Western blotting method. Results: The survival rates of HepG2 cells in 5. 0 and 10. 0 jumol • L_ 1 cyclamin groups were significantly lower than those of HL-7702 cells (P < 0 . 0 5) . The Filipin staining results showed that the cholesterol level in HepG2 cells was higher than that in HL-7702 cells (P < 0 . 0 5) . The LDH release levels in HepG2 cells in cyclamin groups were higher than those in than HL-7702 cells (P < 0 . 0 5) . Compared with 5.0 fxmol • L_ 1 cyclamin group, the LDH release level and the apoptotic rate in cholesterol intervention group were decreased (P < 0 . 0 5) . The Western blotting results showed that the expression levels of Fas, FADD and caspase-8 proteins in HepG2 cells in cyclamin groups were increased compared with control group (P < 0 . 0 5); compared with cyclamin group, the expression levels of Fas, FADD and caspase-8 proteins in cholesterol intervention group were decreased (P < 0 . 0 5) . Conclusion: Cyclamin can selectively inhibit the proliferation of liver cancer cells, and its molecular mechanisms may be related to the increased cell membrane permeabilization via targeting membrane cholesterol component and the consequent ligand-independent activation of Fas signaling pathway.
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PURPOSE: Human leukocyte antigen (HLA) has been recognized as the most important genetic risk factor for severe cutaneous adverse drug reactions (SCARs) caused by certain drugs. However, cumulated observations suggest the presence of genetic risk factors for SCARs other than drug-specific HLA. We aimed to identify a common genetic risk factor of SCARs across multiple drugs. METHODS: We performed 2 independent genome-wide association studies (GWASs). A total of 68 and 38 subjects with a diagnosis of SCAR were enrolled in each GWAS. Their allele frequencies were compared to those of healthy subjects in Korea. RESULTS: No single nucleotide polymorphism (SNP) with genome-wide significance was found in either GWAS. We next selected and annotated the 200 top-ranked SNPs from each GWAS. These 2 sets of annotated genes were then entered into the web interface of ConsensusPathDB for a pathway-level analysis. The Fas signaling pathway was significantly over-represented in each gene set from the 2 GWASs. CONCLUSIONS: Our observations suggest that the Fas signaling pathway may be a common genetic risk factor for SCARs across multiple drugs.
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Red blood cells (RBCs) influence rheology, and release ADP, ATP, and nitric oxide, suggesting a role for RBCs in hemostasis and thrombosis. Here, we provide evidence for a significant contribution of RBCs to thrombus formation. Anemic mice showed enhanced occlusion times upon injury of the carotid artery. A small population of RBCs was located to platelet thrombi and enhanced platelet activation by a direct cell contact via the FasL/FasR (CD95) pathway known to induce apoptosis. Activation of platelets in the presence of RBCs led to platelet FasL exposure that activated FasR on RBCs responsible for externalization of phosphatidylserine (PS) on the RBC membrane. Inhibition or genetic deletion of either FasL or FasR resulted in reduced PS exposure of RBCs and platelets, decreased thrombin generation, and reduced thrombus formation in vitro and protection against arterial thrombosis in vivo. Direct cell contacts between platelets and RBCs via FasL/FasR were shown after ligation of the inferior vena cava (IVC) and in surgical specimens of patients after thrombectomy. In a flow restriction model of the IVC, reduced thrombus formation was observed in FasL-/- mice. Taken together, our data reveal a significant contribution of RBCs to thrombosis by the FasL/FasR pathway.
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Plaquetas/fisiología , Eritrocitos/fisiología , Proteína Ligando Fas/sangre , Trombosis/sangre , Receptor fas/sangre , Anciano , Anciano de 80 o más Años , Anemia/sangre , Animales , Plaquetas/ultraestructura , Comunicación Celular/fisiología , Modelos Animales de Enfermedad , Eritrocitos/ultraestructura , Proteína Ligando Fas/deficiencia , Proteína Ligando Fas/genética , Femenino , Hemorreología/fisiología , Hemostasis/fisiología , Humanos , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Fosfatidilserinas/sangre , Activación Plaquetaria/fisiología , Trombosis/etiología , Trombosis/patologíaRESUMEN
PURPOSE: Human leukocyte antigen (HLA) has been recognized as the most important genetic risk factor for severe cutaneous adverse drug reactions (SCARs) caused by certain drugs. However, cumulated observations suggest the presence of genetic risk factors for SCARs other than drug-specific HLA. We aimed to identify a common genetic risk factor of SCARs across multiple drugs. METHODS: We performed 2 independent genome-wide association studies (GWASs). A total of 68 and 38 subjects with a diagnosis of SCAR were enrolled in each GWAS. Their allele frequencies were compared to those of healthy subjects in Korea. RESULTS: No single nucleotide polymorphism (SNP) with genome-wide significance was found in either GWAS. We next selected and annotated the 200 top-ranked SNPs from each GWAS. These 2 sets of annotated genes were then entered into the web interface of ConsensusPathDB for a pathway-level analysis. The Fas signaling pathway was significantly over-represented in each gene set from the 2 GWASs. CONCLUSIONS: Our observations suggest that the Fas signaling pathway may be a common genetic risk factor for SCARs across multiple drugs.
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Humanos , Cicatriz , Diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Voluntarios Sanos , Corea (Geográfico) , Leucocitos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Síndrome de Stevens-JohnsonRESUMEN
Fas signaling promotes colorectal cancer (CRC) metastasis by inducing epithelial-mesenchymal transition (EMT). The acquisition of EMT properties in turn induces stemness but the mechanism by which Fas signaling contributes to it still remains unclear. Hence, the aim of this study was to investigate how Fas signaling regulates CRC stemness. For this purpose, soft agar assay, sphere formation assay, cell survival analysis, immunoblot, qRT-PCR, chromatin immunoprecipitation, and luciferase reporter assay were performed. Expression of FasL, Bmi1, and the miR-200c in CRC specimens was examined through immunohistochemistry, qRT-PCR, and immunoblot. In our study, Fas signaling induced stem cell properties in CRC specimens, relying on ERK1/2 MAPK pathway, with Bmi1 being mainly responsible for FasL-induced stemness. FasL treatment promoted Bmi1 expression by inhibiting miR-200c, which targets Bmi1 3'UTR region. Furthermore, FasL-induced Zeb1 binded with miR-200c promoter and inhibited its expression. Moreover, FasL-induced ß-catenin nuclear expression promoted Zeb1 expression by binding with Zeb1 promoter. GSK-3ß, which regulates ß-catenin, was inhibited by FasL-induced ERK1/2 MAPK signaling. Finally, FasL and Bmi1 expression in clinical samples increased during CRC progression, and a positive correlation between them was observed. Patients with high FasL and Bmi1 expression had a worse prognosis than patients with low expression. In conclusion, our results showed that Fas signaling can promote stemness in CRC through the modulation of Bmi1 expression via the ERK1/2 MAPK/GSK-3ß/ß-catenin/Zeb1/miR-200c axis, suggesting that Fas signaling-based cancer therapies should be administered cautiously, as the activation of this pathway not only leads to apoptosis but also induces stemness in CRC.
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Neoplasias Colorrectales/genética , Proteína Ligando Fas/farmacología , MicroARNs/genética , Células Madre Neoplásicas/efectos de los fármacos , Complejo Represivo Polycomb 1/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Regiones no Traducidas 3' , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Neoplasias Colorrectales/metabolismo , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Humanos , Células Madre Neoplásicas/metabolismo , Complejo Represivo Polycomb 1/metabolismo , Regiones Promotoras Genéticas , Transducción de Señal , beta Catenina/metabolismoRESUMEN
Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank-truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (p = 5.5E-04) and GCA (p = 6.3E-03), but not GNCA (p= 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal p < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal p< 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations.