RESUMO
Activation of IL-4R (IL-4 receptor) signaling in airway epithelial cells leads to airway hyperresponsiveness and mucus overproduction in asthma. CDH26 (cadherin-26), a cadherin implicated in the polarization of airway epithelial cells, is upregulated in asthma. However, the role of CDH26 in asthma remains unknown. In this study, we demonstrated that Cdh26 deficiency significantly reduced airway mucus overproduction, airway hyperresponsiveness, and airway eosinophilia in a murine model of allergic airway disease. Interestingly, allergen-induced Il-4Rα upregulation in airway epithelium was markedly reduced in Cdh26-/- mice. In cultured human bronchial epithelial cells, CDH26 knockdown inhibited IL-13, a ligand for IL-4R; induced IL-4Rα and IL-13Rα1 (IL-13 receptor α1) upregulation; and suppressed downstream Jak1 (Janus kinase 1) and Stat6 (signal transducer and activator of transcription 6) phosphorylation. Moreover, CDH26 knockdown inhibited IL-13-induced MUC5AC and eosinophilic chemokine expression. These results suggest that CDH26 plays a key role in epithelial IL-4R signaling activation and downstream effectors. In contrast, CDH26 overexpression amplified IL-13-activated IL-4R signaling in BEAS-2B cells. In the airway epithelium of patients with asthma, IL-4Rα expression was elevated, and CDH26 was the only cadherin that was upregulated among 11 cadherin family members. CDH26 expression was strongly correlated with epithelial IL-4Rα and MUC5AC expression, sputum eosinophilia, and fractional exhaled nitric oxide in patients with asthma. Taken together, we identified CDH26 as a key regulator of epithelial IL-4R signaling in asthma and a potential therapeutic target for IL-4R-mediated allergic diseases.
Assuntos
Asma , Eosinofilia , Hipersensibilidade , Humanos , Camundongos , Animais , Interleucina-13 , Receptores de Interleucina-4 , Asma/metabolismo , Hipersensibilidade/metabolismo , CaderinasRESUMO
BACKGROUND: Owing to the high morbidity and mortality, ovarian cancer has seriously endangered female health. Development of reliable models can facilitate prognosis monitoring and help relieve the distress. METHODS: Using the data archived in the TCPA and TCGA databases, proteins having significant survival effects on ovarian cancer patients were screened by univariate Cox regression analysis. Patients with complete information concerning protein expression, survival, and clinical variables were included. A risk model was then constructed by performing multiple Cox regression analysis. After validation, the predictive power of the risk model was assessed. The prognostic effect and the biological function of the model were evaluated using co-expression analysis and enrichment analysis. RESULTS: 394 patients were included in model construction and validation. Using univariate Cox regression analysis, we identified a total of 20 proteins associated with overall survival of ovarian cancer patients (p < 0.01). Based on multiple Cox regression analysis, six proteins (GSK3α/ß, HSP70, MEK1, MTOR, BAD, and NDRG1) were used for model construction. Patients in the high-risk group had unfavorable overall survival (p < 0.001) and poor disease-specific survival (p = 0.001). All these six proteins also had survival prognostic effects. Multiple Cox regression analysis demonstrated the risk model as an independent prognostic factor (p < 0.001). In receiver operating characteristic curve analysis, the risk model displayed higher predictive power than age, tumor grade, and tumor stage, with an area under the curve value of 0.789. Analysis of co-expressed proteins and differentially expressed genes based on the risk model further revealed its prognostic implication. CONCLUSIONS: The risk model composed of GSK3α/ß, HSP70, MEK1, MTOR, BAD, and NDRG1 could predict survival prognosis of ovarian cancer patients efficiently and help disease management.
Assuntos
Neoplasias Ovarianas , RNA Longo não Codificante , Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Prognóstico , RNA Longo não Codificante/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: Ovarian cancer has greatly endangered and deteriorated female health conditions worldwide. Refinement of predictive biomarkers could enable patient stratification and help optimize disease management. METHODS: RAD51 expression profile, target-disease associations, and fitness scores of RAD51 were analyzed in ovarian cancer using bioinformatic analysis. To further identify its role, gene enrichment analysis was performed, and a regulatory network was constructed. Survival analysis and drug sensitivity assay were performed to evaluate the effect of RAD51 expression on ovarian cancer prognosis. The predictive value of RAD51 was then confirmed in a validation cohort immunohistochemically. RESULTS: Ovarian cancer expressed more RAD51 than normal ovary. RAD51 conferred ovarian cancer dependency and was associated with ovarian cancer. RAD51 had extensive target-disease associations with various diseases, including ovarian cancer. Genes that correlate with and interact with RAD51 were involved in DNA damage repair and drug responsiveness. High RAD51 expression indicated unfavorable survival outcomes and resistance to platinum, taxane, and PARP inhibitors in ovarian cancer. In the validation cohort (126 patients), high RAD51 expression indicated platinum resistance, and platinum-resistant patients expressed more RAD51. Patients with high RAD51 expression had shorter OS (HR = 2.968, P < 0.0001) and poorer PFS (HR = 2.838, P < 0.0001). RAD51 expression level was negatively correlated with patients' survival length. CONCLUSIONS: Ovarian cancer had pronounced RAD51 expression and RAD51 conferred ovarian cancer dependency. High RAD51 expression indicated poor survival and decreased drug sensitivity. RAD51 has predictive value in ovarian cancer and can be exploited as a predictive biomarker.
RESUMO
The etiology of hair loss remains enigmatic, and current remedies remain inadequate. Transcriptome analysis of aging hair follicles uncovered changes in immune pathways, including Toll-like receptors (TLRs). Our findings demonstrate that the maintenance of hair follicle homeostasis and the regeneration capacity after damage depend on TLR2 in hair follicle stem cells (HFSCs). In healthy hair follicles, TLR2 is expressed in a cycle-dependent manner and governs HFSCs activation by countering inhibitory BMP signaling. Hair follicles in aging and obesity exhibit a decrease in both TLR2 and its endogenous ligand carboxyethylpyrrole (CEP), a metabolite of polyunsaturated fatty acids. Administration of CEP stimulates hair regeneration through a TLR2-dependent mechanism. These results establish a novel connection between TLR2-mediated innate immunity and HFSC activation, which is pivotal to hair follicle health and the prevention of hair loss and provide new avenues for therapeutic intervention.
Assuntos
Folículo Piloso , Receptor 2 Toll-Like , Humanos , Cabelo , AlopeciaRESUMO
The etiology of hair loss remains enigmatic, and current remedies remain inadequate. Transcriptome analysis of aging hair follicles uncovered changes in immune pathways, including Toll-like receptors (TLRs). Our findings demonstrate that the maintenance of hair follicle homeostasis and the regeneration capacity after damage depends on TLR2 in hair follicle stem cells (HFSCs). In healthy hair follicles, TLR2 is expressed in a cycle-dependent manner and governs HFSCs activation by countering inhibitory BMP signaling. Hair follicles in aging and obesity exhibit a decrease in both TLR2 and its endogenous ligand carboxyethylpyrrole (CEP), a metabolite of polyunsaturated fatty acids. Administration of CEP stimulates hair regeneration through a TLR2-dependent mechanism. These results establish a novel connection between TLR2-mediated innate immunity and HFSC activation, which is pivotal to hair follicle health and the prevention of hair loss and provide new avenues for therapeutic intervention.
RESUMO
OBJECTIVE: It is unclear why adhesion-dependent cells such as epithelium undergo anoikis without anchorage, while adhesion-independent blood cells thrive in suspension. The adhesive machinery of these cells is similar, with the exception of Kindlin orthologs, Kindlin 2 (K2) and Kindlin 3 (K3). Here we address how Kindlins control cell survival and proliferation in anchorage-dependent and independent cells. MATERIAL AND METHODS: To demonstrate the opposite roles of Kindlin's in cell survival we utilized in vivo and in vitro models and K3 and K2 knockdown and knockin cells. We used human lymphocytes from the K3 deficient patients in tumour model, K3 knockout and knockin macrophages and K2 knockout and knockin MEF cells for experiments in under conditions of adhesion and in suspension. RESULTS: Depletion of K3 promotes cell proliferation and survival of anchorage-independent cells regardless of cell attachment. In contrast, the absence of K2 in anchorage-dependent cells accelerates apoptosis and limits proliferation. K3 deficiency promotes human lymphoma growth and survival in vivo. Kindlins' interaction with paxillin, is critical for their differential roles in cell anchorage. While disruption of K2-paxillin binding leads to increased apoptosis, the lack of K3-paxillin binding has an opposite effect in adhesion-independent cells. CONCLUSION: Kindlin ortologs and their interaction to cytoskeletal protein paxillin define the mechanisms of anchorage dependence. Our study identifies the key elements of the cell adhesion machinery in cell survival and tumour metastasis, proposing possible targets for tumour treatment.
Assuntos
Proteínas do Citoesqueleto , Adesão Celular , Proliferação de Células , Sobrevivência Celular , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Humanos , Paxilina/metabolismoRESUMO
As a part of innate immunity, toll-like receptor 2 (TLR2) plays an important function in most defensive responses of the organism, including but not limited to infections. Cutaneous injury, one of the most common challenges for mammals, mobilizes a number of cell types, including epithelial, immune, and vascular cells, for timely tissue repair. However, in contrast to immune cells, little is known about TLR2 function on nonimmune cells during skin regeneration. In this study, we used two tissue-specific conditional Tlr2-knockout mouse lines to address the effects of TLR2 in endothelial and hair follicle stem cells (HFSCs) on cutaneous wound healing. The loss of TLR2 on endothelial cells diminishes their ability to migrate, sprout, and proliferate in response to specific TLR2 ligands and also reduces the secretion of key proangiogenic factors. Lack of TLR2 on endothelial cells prolongs wound healing owing to diminished angiogenesis. TLR2 is expressed in key structures of hair follicles, including HFSCs, secondary hair germ, and dermal papilla. Despite the prominent role of HFSCs in skin regeneration, excision of TLR2 from HFSCs has no effects on their proliferation or wound healing potential. Our study shows that timely tissue regeneration after skin injury is dependent on endothelial TLR2 for robust angiogenesis, whereas HFSC TLR2 is dispensable.
Assuntos
Folículo Piloso , Células-Tronco , Receptor 2 Toll-Like , Cicatrização , Animais , Camundongos , Células Endoteliais , Folículo Piloso/fisiologia , Neovascularização Patológica , Células-Tronco/fisiologia , Receptor 2 Toll-Like/genética , Cicatrização/fisiologiaRESUMO
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, with poor prognosis and no cure. Substantial evidence implicates inflammation and associated oxidative stress as a potential mechanism for ALS, especially in patients carrying the SOD1 mutation and, therefore, lacking anti-oxidant defense. The brain is particularly vulnerable to oxidation due to the abundance of polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), which can give rise to several oxidized metabolites. Accumulation of a DHA peroxidation product, CarboxyEthylPyrrole (CEP) is dependent on activated inflammatory cells and myeloperoxidase (MPO), and thus marks areas of inflammation-associated oxidative stress. At the same time, generation of an alternative inactive DHA peroxidation product, ethylpyrrole, does not require cell activation and MPO activity. While absent in normal brain tissues, CEP is accumulated in the central nervous system (CNS) of ALS patients, reaching particularly high levels in individuals carrying a SOD1 mutation. ALS brains are characterized by high levels of MPO and lowered anti-oxidant activity (due to the SOD1 mutation), thereby aiding CEP generation and accumulation. Due to DHA oxidation within the membranes, CEP marks cells with the highest oxidative damage. In all ALS cases CEP is present in nearly all astrocytes and microglia, however, only in individuals carrying a SOD1 mutation CEP marks >90% of neurons, thereby emphasizing an importance of CEP accumulation as a potential hallmark of oxidative damage in neurodegenerative diseases.
Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Esclerose Lateral Amiotrófica/genética , Animais , Modelos Animais de Doenças , Humanos , Inflamação/genética , Camundongos , Camundongos Transgênicos , Mutação , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/genéticaRESUMO
Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer worldwide, and appropriate cancer biomarkers facilitate early diagnosis, treatment, and prognosis prediction in cancer management. However, an accurate biomarker for ccRCC is lacking. This study identified 356 differentially expressed genes in ccRCC tissues compared with normal kidney tissues by integrative analysis of eight ccRCC datasets. Enrichment analysis of the differentially expressed genes unveiled improved adaptation to hypoxia and metabolic reprogramming of the tumor cells. Aldehyde oxidase 1 (AOX1) gene was identified as a biomarker for ccRCC among all the differentially expressed genes. ccRCC tissues expressed significantly lower AOX1 than normal kidney tissues, which was further validated by immunohistochemistry at the protein level and The Cancer Genome Atlas (TCGA) data mining at the mRNA level. Higher AOX1 expression predicted better overall survival in ccRCC patients. Furthermore, AOX1 DNA copy number deletion and hypermethylation were negatively correlated with AOX1 expression, which might be the potential mechanism for its dysregulation in ccRCC. Finally, we illustrated that the effect of AOX1 as a tumor suppressor gene is not restricted to ccRCC but universally exists in many other cancer types. Hence, AOX1 may act as a potential prognostic biomarker and therapeutic target for ccRCC.
RESUMO
Acute aortic dissection (AAD) is a life-threatening disease. Despite the higher risk of mortality, currently there are no effective therapies that can ameliorate AAD development or progression. Identification of meaningful clusters of co-expressed genes or representative biomarkers for AAD may help to identify new pathomechanisms and foster development of new therapies. To this end, we performed a weighted gene co-expression network analysis (WGCNA) and calculated module-trait correlations based on a public microarray dataset (GSE 52093) and discovered 9 modules were found to be related to AAD. The module which has the strongest positive correlation with AAD was further analyzed and the top 10 hub genes SLC20A1, GINS2, CNN1, FAM198B, MAD2L2, UBE2T, FKBP11, SLMAP, CCDC34, and GALK1 were identified. Furthermore, we validated the data by qRT-PCR in an independent sample set originated from our study center. Overall, the qRT-PCR results were consistent with the results of the microarray analysis. Intriguingly, the highest change was found for FKBP11, a protein belongs to the FKBP family of peptidyl-prolyl cis/trans isomerases, which catalyze the folding of proline-containing polypeptides. In congruent with the gene expression analysis, FKBP11 expression was induced in cultured endothelial cells by angiotensin II treatment and endothelium of the dissected aorta. More importantly we show that FKBP11 provokes inflammation in endothelial cells by interacting with NF-kB p65 subunit, resulting in pro-inflammatory cytokines production. Accordingly, siRNA mediated knockdown of FKBP11 in cultured endothelial cells suppressed angiotensin II induced monocyte transmigration through the endothelial monolayer. Based on these data, we hypothesize that pro-inflammatory cytokines elicited by FKBP11 overexpression in the endothelium under AAD condition could facilitate transendothelial migration of the circulating monocytes into the aorta, where they differentiate into active macrophages and secrete MMPs and other extracellular matrix (ECM) degrading proteins, contributing to sustained inflammation and AAD. Taken together, our data identify important role of FKBP11 which can serve as biomarker and/or therapeutic target for AAD.