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1.
Life Sci ; 243: 117295, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31927050

RESUMO

More than 140 thousands of women suffer from endometrial carcinoma in the worldwide, and over 40 thousand of the patients die before and after in surgery and chemoradiotherapy because of its metastasis. However, its molecular mechanism is much less known compared to other cancers. In this study, we demonstrated that long non-coding RNA PCAT1 is dramatically increased in the tissues and plasma from endometrial carcinoma (EC) (n = 100, all p < 0.001) controlled by its paracancerous tissue, and cell lines including RL-952, HEC-1-B, KLE, Ishikawa, and AN3CA compared to the cells from normal endometrium (all p < 0.001). When lncRNA PCAT1 was knocked-down, the KLE and AN3CA cells exhibited slow capability on proliferation and colony formation in vitro. With the silence of lncRNA PCAT1, the cells were markedly inhibited on migration and invasion in vitro (all p < 0.001), which were confirmed on the EC patient subjects. When expressions of lncRNA PCAT1 were interfered in the cells, expressions of E-cadherin but not N-cadherin and Vimentin were significantly promoted with a strong up-regulation accompanied by nearly completed recoveries on migration and invasion (all p < 0.001). In order to analyze the association of lncRNA PCAT1 and E-cadherin, we silenced the expressions of both genes and unveiled that EC migration and invasion were significantly congested (all p < 0.001). Importantly, we found that the E-cadherin down-regulation caused by lncRNA PCAT1 associates with histone methyltransferase EZH2. When over-expression of EZH2 was applied in the PCAT1 silenced cells, the expression of E-cadherin experienced significant decrease in the cell lines. Reversely, when expression of EZH2 was annulled in the PCAT1 silenced cells, the expression of E-cadherin was significantly boosted in the cells (all p < 0.001). Furthermore, the interaction of lncRNA PCAT1 and EZH2 were approved with immunoprecipitation. Our data demonstrated that the methyltransferase EZH2 related up-regulation of lncRNA PCAT1 along with down-regulation of E-cadherin could be essential in oncogenesis of endometrial carcinoma in both EC cells and patient subjects. These compact data suggest that combination of lncRNA PCAT1, EZH2 and E-cadherin could provide valued information for efficient EC diagnostics, which would propose a potential target for EC treatment with EZH2i on methyltransferation.


Assuntos
Caderinas/fisiologia , Regulação para Baixo/genética , Neoplasias do Endométrio/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Metástase Neoplásica/genética , RNA Longo não Codificante/fisiologia , Animais , Linhagem Celular Tumoral , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/genética , Feminino , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Ligação Proteica , RNA Longo não Codificante/metabolismo
2.
Rev Soc Bras Med Trop ; 52: e20180353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31778418

RESUMO

INTRODUCTION: Dengue is an important mosquito-borne disease in tropical and subtropical regions. Adhesion molecules have not been systematically characterized in the renal tissue of patients with severe dengue (SD). The objective of this study was to detect viral antigens in samples from patients that evolved with SD, correlating with the expression of ICAM-1, VCAM-1, VE-cadherin, and E-selectin to contribute to a better understanding of the pathophysiology of SD. METHODS: Kidney specimens from patients with SD were selected according to clinical and laboratorial data and submitted to histological and immunohistochemistry analysis. A semiquantitative evaluation was performed considering positive immunostaining in 20 glomeruli. RESULTS: Viral antigens were mainly detected in distal tubules. The intense immunostaining of VCAM-1 and ICAM-1 was observed. The expression of E-selectin was discrete, and VE-cadherin expression varied from mild to moderate. VCAM-1 was slightly intense in the glomerular capsule; the expression of ICAM-1 was diffuse. E-selectin was diffuse, and VE-cadherin varied from mild to moderate. The most frequent histological findings were glomerular congestion, mild glomerulitis, acute renal injury, and glomerular atrophy. CONCLUSIONS: The results appear to demonstrate an imbalance between vascular endothelial permeability regulating events in renal lesions in SD. The increase in the expression of ICAM-1 and VCAM-1 is an in-situ indicator of higher permeability with a consequent influx of cells favoring the inflammation of the endothelium. These molecules are important in the pathophysiology of the disease and provide the possibility of developing new markers for the evaluation, clinical follow-up, and therapeutic response of patients with SD.


Assuntos
Selectina E/fisiologia , Endotélio/fisiopatologia , Molécula 1 de Adesão Intercelular/fisiologia , Dengue Grave/sangue , Dengue Grave/fisiopatologia , Molécula 1 de Adesão de Célula Vascular/fisiologia , Adolescente , Adulto , Antígenos CD/sangue , Antígenos CD/fisiologia , Antígenos Virais/sangue , Biomarcadores/sangue , Caderinas/sangue , Caderinas/fisiologia , Criança , Pré-Escolar , Progressão da Doença , Selectina E/sangue , Feminino , Humanos , Imuno-Histoquímica , Molécula 1 de Adesão Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Regulação para Cima , Molécula 1 de Adesão de Célula Vascular/sangue , Adulto Jovem
3.
Nat Rev Dis Primers ; 5(1): 18, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872586

RESUMO

The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30-40% in most studies. Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-resourced settings and in paediatric patients. Treatment focuses on lung-protective ventilation; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.


Assuntos
Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Lesão Pulmonar Induzida por Ventilação Mecânica/complicações , Angiopoietina-2/análise , Antígenos CD/fisiologia , Biomarcadores/análise , Caderinas/fisiologia , Dióxido de Carbono/análise , Dióxido de Carbono/metabolismo , Glucocorticoides/uso terapêutico , Ventilação de Alta Frequência/métodos , Humanos , Interleucina-8/análise , Respiração com Pressão Positiva/métodos , Qualidade de Vida/psicologia , Radiografia/métodos , Respiração Artificial/efeitos adversos , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório do Adulto/epidemiologia , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Vasodilatadores/uso terapêutico , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia , Fator de von Willebrand/análise
4.
Circ Res ; 124(6): 891-903, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30707047

RESUMO

RATIONALE: Endothelial barrier function depends on the proper localization and function of the adherens junction protein VE (vascular endothelial)-cadherin. Previous studies have suggested a functional relationship between integrin-mediated adhesion complexes and VE-cadherin yet the underlying molecular links are unclear. Binding of the cytoskeletal adaptor protein talin to the ß-integrin cytoplasmic domain is a key final step in regulating the affinity of integrins for extracellular ligands (activation) but the role of integrin activation in VE-cadherin mediated endothelial barrier function is unknown. OBJECTIVE: To test the requirement of talin-dependent activation of ß1 integrin in VE-cadherin organization and endothelial cell (EC) barrier function. METHODS AND RESULTS: EC-specific deletion of talin in adult mice resulted in impaired stability of intestinal microvascular blood vessels, hemorrhage, and death. Talin-deficient endothelium showed altered VE-cadherin organization at EC junctions in vivo. shRNA (short hairpin RNA)-mediated knockdown of talin1 expression in cultured ECs led to increased radial actin stress fibers, increased adherens junction width and increased endothelial monolayer permeability measured by electrical cell-substrate impedance sensing. Restoring ß1-integrin activation in talin-deficient cells with a ß1-integrin activating antibody normalized both VE-cadherin organization and EC barrier function. In addition, VE-cadherin organization was normalized by reexpression of talin or integrin activating talin head domain but not a talin head domain mutant that is selectively deficient in activating integrins. CONCLUSIONS: Talin-dependent activation of EC ß1-integrin stabilizes VE-cadherin at endothelial junctions and promotes endothelial barrier function.


Assuntos
Antígenos CD/fisiologia , Caderinas/fisiologia , Células Endoteliais/fisiologia , Integrina beta1/fisiologia , Talina/fisiologia , Animais , Antígenos CD/análise , Caderinas/análise , Feminino , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Junções Intercelulares/metabolismo , Masculino , Camundongos
5.
Hum Cell ; 32(2): 95-102, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30674001

RESUMO

To clarify the potential role of gap junction in cell-cell contact response, the expression of connexin30.3 gene (Cx30.3), a specifically expressed isoform in undifferentiated state of mouse embryonic stem (ES) cell line EB3 was investigated under different cell-cell contact conditions. ES cells were cultured by hanging drop culture method to increase cell-cell contact frequency. As control, a single cell culture was conducted. After culture for 12 h, the Cx30.3 expression level in hanging drop culture reached 1.73-fold that of the control (p < 0.001). By contrast, connexin43 gene (Cx43), a ubiquitously expressed gene, showed no difference between both cultures. The experiment of E-cadherin inhibition and ß-catenin knockdown suggested the action of E-cadherin upstream of the Cx30.3 regulating pathway. The cell-cell contacts with different cell lines such as HeLa cells and B16/BL6 caused no effect on the Cx30.3 in ES cells. These suggest a potential role of Cx30.3 as a cell-cell contact signal mediator partially regulated by E-cadherin signaling.


Assuntos
Caderinas/fisiologia , Comunicação Celular/genética , Técnicas de Cultura de Células/métodos , Conexinas/genética , Conexinas/metabolismo , Expressão Gênica , Células-Tronco Embrionárias Murinas/fisiologia , Animais , Linhagem Celular , Regulação da Expressão Gênica , Camundongos , Transdução de Sinais/fisiologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-30598410

RESUMO

OBJECTIVE: The aim of this study was to evaluate the expression of Twist and E-cadherin in lower lip squamous cell carcinoma (LLSCC) and their association with clinicopathologic parameters. STUDY DESIGN: Fifty-nine cases of LLSCC were analyzed by applying immunohistochemistry techniques in a semiquantitative manner. The systems proposed by Bryne etal., Brandwein-Gensler etal., and Almangush etal. were applied for analysis of the histopathologic malignancy grading system. RESULTS: Higher E-cadherin expression (general and membrane) was observed in cases presenting with disease-free survival after 5years of follow-up (P < .05). Higher Twist expression was observed in lesions classified as being in advanced stages, displaying recurrence, and having a high degree of malignancy. A significant negative correlation was detected between cytoplasmic Twist expression and membrane E-cadherin expression (P = .028). A statistically significant relationship was detected between high total Twist expression in tumors classified as high risk by Brandwein-Gensler etal., and no significant difference was observed among total, membrane, and cytoplasmic E-cadherin expressions in LLSCC cases and the 3 applied grading systems (P > .05). CONCLUSIONS: The results of the present study suggest the potential involvement of Twist and E-cadherin in the modulation of events related to worse prognoses in LLSCC cases.


Assuntos
Antígenos CD , Caderinas , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Labiais , Proteínas Nucleares , Proteína 1 Relacionada a Twist , Antígenos CD/metabolismo , Antígenos CD/fisiologia , Biomarcadores Tumorais , Caderinas/metabolismo , Caderinas/fisiologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Humanos , Lábio , Neoplasias Labiais/metabolismo , Neoplasias Labiais/patologia , Recidiva Local de Neoplasia , Proteínas Nucleares/metabolismo , Prognóstico , Proteína 1 Relacionada a Twist/metabolismo
7.
Carcinogenesis ; 40(1): 15-26, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30508037

RESUMO

Histone modification plays important molecular roles in development and progression of cancers. Dysregulation of histone H3 arginine (R) methylation is still unknown in primary cancer, including gastric cancer (GC). Although PRMT6 contributes to asymmetric dimethylation at H3R2 (H3R2me2as) in cancer cells, its molecular functions are poorly understood in GC. In this study, we assessed H3R2me2as and PRMT6 expression levels in 133 primary GC tissues by immunohistochemistry. Increased H3R2me2as was found in 68 GC (51.1%) cases and independently related to poor prognosis. PRMT6 was overexpressed in 70 GC (52.6%) and strongly correlated with the global H3R2me2as levels (P < 0.001). By analyzing biological functions of PRMT6 in GC cell lines by lentivirus-based systems, PRMT6 overexpression enhanced global H3R2me2as and invasiveness in vitro, while PRMT6 knockout (PRMT6-KO) suppressed these effects and tumorigenicity in vivo. ChIP and microarray assays demonstrated that PRMT6-KO GC cells decreased the enrichments of H3R2me2as at the promoter regions of PCDH7, SCD and IGFBP5, resulting in upregulation of their gene expression. PRMT6 was recruited to the promoter regions of PCDH7 and SCD in the PRMT6-overexpressed cells. Knockdown of tumor suppressor PCDH7 in the PRMT6-KO GC cells elevated cell migration and invasion. PRMT6 expression inversely correlated with PCDH7 expression in primary GC (P = 0.021). Collectively, our findings strongly indicate that H3R2me2as is a strong prognostic indicator of GC patients, and PRMT6-overexpressing GC cells may acquire invasiveness through direct transcriptional inhibition of PCDH7 by increasing H3R2me2as level. Thus, inhibition of the PRMT6-H3R2me2as pathway could be a promising new therapeutic strategy in GC.


Assuntos
Histonas/metabolismo , Proteínas Nucleares/fisiologia , Proteína-Arginina N-Metiltransferases/fisiologia , Neoplasias Gástricas/metabolismo , Animais , Arginina/metabolismo , Caderinas/antagonistas & inibidores , Caderinas/fisiologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Masculino , Metilação , Camundongos , Neoplasias Gástricas/patologia
8.
Biochem Biophys Res Commun ; 508(2): 543-549, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30509494

RESUMO

Liver fibrosis, an important health condition associated with chronic liver injury that provides a permissive environment for cancer development, is characterized by the persistent deposition of extracellular matrix components that are mainly derived from activated hepatic stellate cells (HSCs). CDH11 belongs to a group of transmembrane proteins that are principally located in adherens junctions. CDH11 mediates homophilic cell-to-cell adhesion, which may promote the development of cirrhosis. The goal of this study was to determine whether CDH11 regulates liver fibrosis and to examine its mechanism by focusing on HSC activation. Here we demonstrate that CDH11 expression is elevated in human and mouse fibrotic liver tissues and that CDH11 mediates the profibrotic response in activated HSCs. Our data indicate that CDH11 regulates the TGFß-induced activation of HSCs. Moreover, cells from CDH11 deficient mice displayed decreased HSC activation in vitro, and CDH11 deficient mice developed liver fibrogenesis in response to chronic damage induced by CCl4 administration. In addition, CDH11 expression was positively correlated with liver fibrosis in patients with cirrhosis, and could therefore be a prognostic factor in patients with liver fibrosis. Collectively, our findings demonstrate that CDH11 promotes liver fibrosis by activating HSCs and may represent a potential target for anti-fibrotic therapies.


Assuntos
Caderinas/fisiologia , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/etiologia , Animais , Tetracloreto de Carbono/farmacologia , Células Cultivadas , Humanos , Camundongos , Prognóstico , Fator de Crescimento Transformador beta
9.
Mol Biol Cell ; 30(1): 108-118, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30403560

RESUMO

Transporting epithelial cells optimize their morphology for solute uptake by building an apical specialization: a dense array of microvilli that serves to increase membrane surface area. In the intestinal tract, individual cells build thousands of microvilli, which pack tightly to form the brush border. Recent studies implicate adhesion molecule CDHR2 in the regulation of microvillar packing via the formation of adhesion complexes between the tips of adjacent protrusions. To gain insight on how CDHR2 contributes to brush border morphogenesis and enterocyte function under native in vivo conditions, we generated mice lacking CDHR2 expression in the intestinal tract. Although CDHR2 knockout (KO) mice are viable, body weight trends lower and careful examination of tissue, cell, and brush border morphology revealed several perturbations that likely contribute to reduced functional capacity of KO intestine. In the absence of CDHR2, microvilli are significantly shorter, and exhibit disordered packing and a 30% decrease in packing density. These structural perturbations are linked to decreased levels of key solute processing and transporting factors in the brush border. Thus, CDHR2 functions to elongate microvilli and maximize their numbers on the apical surface, which together serve to increase the functional capacity of enterocyte.


Assuntos
Caderinas/metabolismo , Microvilosidades/fisiologia , Animais , Biomarcadores/metabolismo , Peso Corporal , Caderinas/genética , Caderinas/fisiologia , Enterócitos/citologia , Enterócitos/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Camundongos Knockout , Microvilosidades/ultraestrutura
10.
J Contemp Dent Pract ; 19(9): 1105-1110, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30287712

RESUMO

AIM: The aim of present study was to assess the role of E-cadherin in oral carcinogenesis by comparing their expressions in normal oral mucosa, oral epithelial dysplasia (OED), and oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: To elucidate the pattern of E-cadherin expression in oral carcinogenesis, 21 archival cases of formalin-fixed paraffin-embedded sections of OSCC, 21 OED, and 7 normal oral mucosa samples as control were used for the study. RESULTS: We observed reduction/loss of E-cadherin in membranous expression pattern and staining intensity with progression from dysplasia to oral cancer. CONCLUSION: A decrease in staining intensity and loss of E-cadherin membranous expression were noted from dysplasia to carcinoma, suggesting its role as a tumor suppressor gene. CLINICAL SIGNIFICANCE: E-cadherin can be used as a biomarker to assess and evaluate the progression and prognosis of oral dysplastic lesions and OSCC.


Assuntos
Caderinas/genética , Caderinas/fisiologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Carcinogênese/genética , Carcinoma de Células Escamosas/diagnóstico por imagem , Progressão da Doença , Expressão Gênica , Humanos , Imuno-Histoquímica , Mucosa Bucal/metabolismo , Neoplasias Bucais/diagnóstico , Prognóstico , Estudos Retrospectivos
11.
Cell Rep ; 25(3): 702-714.e6, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332649

RESUMO

CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways. Interestingly, these tumors show enhanced Rac1- and Yap-dependent transcription and signaling, as well as sensitivity to PI3K, Rac1, and Yap inhibitors in culture. Finally, high-dimensional immunophenotyping in control mouse mammary gland and IR-ILC tumors by mass cytometry shows dramatic alterations in myeloid and lymphoid populations associated with immune suppression and exhaustion, highlighting the potential for therapeutic intervention via immune checkpoint regulators.


Assuntos
Caderinas/fisiologia , Carcinoma Lobular/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Animais/patologia , Mutação , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Lobular/imunologia , Carcinoma Lobular/metabolismo , Proteínas de Ciclo Celular/metabolismo , Feminino , Neoplasias Mamárias Animais/imunologia , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Knockout , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Invasividade Neoplásica , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Transcriptoma , Proteínas rac de Ligação ao GTP/metabolismo
12.
BMC Cancer ; 18(1): 939, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30285678

RESUMO

In many types of solid tumours, the aberrant expression of the cell adhesion molecule N-cadherin is a hallmark of epithelial-to-mesenchymal transition, resulting in the acquisition of an aggressive tumour phenotype. This transition endows tumour cells with the capacity to escape from the confines of the primary tumour and metastasise to secondary sites. In this review, we will discuss how N-cadherin actively promotes the metastatic behaviour of tumour cells, including its involvement in critical signalling pathways which mediate these events. In addition, we will explore the emerging role of N-cadherin in haematological malignancies, including bone marrow homing and microenvironmental protection to anti-cancer agents. Finally, we will discuss the evidence that N-cadherin may be a viable therapeutic target to inhibit cancer metastasis and increase tumour cell sensitivity to existing anti-cancer therapies.


Assuntos
Antineoplásicos/uso terapêutico , Caderinas/fisiologia , Neoplasias Hematológicas/fisiopatologia , Metástase Neoplásica/fisiopatologia , Neoplasias/tratamento farmacológico , Caderinas/metabolismo , Movimento Celular/fisiologia , Humanos , Invasividade Neoplásica/fisiopatologia , Neoplasias/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/fisiologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia , Via de Sinalização Wnt/fisiologia
13.
Nat Commun ; 9(1): 3545, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-30171187

RESUMO

Angiogenesis and vascular remodeling are driven by extensive endothelial cell movements. Here, we present in vivo evidence that endothelial cell movements are associated with oscillating lamellipodia-like structures, which emerge from cell junctions in the direction of cell movements. High-resolution time-lapse imaging of these junction-based lamellipodia (JBL) shows dynamic and distinct deployment of junctional proteins, such as F-actin, VE-cadherin and ZO1, during JBL oscillations. Upon initiation, F-actin and VE-cadherin are broadly distributed within JBL, whereas ZO1 remains at cell junctions. Subsequently, a new junction is formed at the front of the JBL, which then merges with the proximal junction. Rac1 inhibition interferes with JBL oscillations and disrupts cell elongation-similar to a truncation in ve-cadherin preventing VE-cad/F-actin interaction. Taken together, our observations suggest an oscillating ratchet-like mechanism, which is used by endothelial cells to move over each other and thus provides the physical means for cell rearrangements.


Assuntos
Actinas/metabolismo , Antígenos CD/fisiologia , Caderinas/fisiologia , Movimento Celular/fisiologia , Células Endoteliais/fisiologia , Pseudópodes/fisiologia , Animais , Animais Geneticamente Modificados , Comunicação Celular/fisiologia , Embrião não Mamífero , Junções Intercelulares/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
14.
Proc Natl Acad Sci U S A ; 115(42): 10556-10563, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30262652

RESUMO

Prior studies demonstrate that astrotactin (ASTN1) provides a neuronal receptor for glial-guided CNS migration. Here we report that ASTN1 binds N-cadherin (CDH2) and that the ASTN1:CDH2 interaction supports cell-cell adhesion. To test the function of ASTN1:CDH2 binding in glial-guided neuronal migration, we generated a conditional loss of Cdh2 in cerebellar granule cells and in glia. Granule cell migration was slowed in cerebellar slice cultures after a conditional loss of neuronal Cdh2, and more severe migration defects occurred after a conditional loss of glial Cdh2 Expression in granule cells of a mutant form of ASTN1 that does not bind CDH2 also slowed migration. Moreover, in vitro chimeras of granule cells and glia showed impaired neuron-glia attachment in the absence of glial, but not neuronal, Cdh2 Thus, cis and trans bindings of ASTN1 to neuronal and glial CDH2 form an asymmetric neuron-glial bridge complex that promotes glial-guided neuronal migration.


Assuntos
Caderinas/fisiologia , Adesão Celular , Movimento Celular , Cerebelo/fisiologia , Glicoproteínas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/fisiologia , Neurônios/fisiologia , Animais , Células Cultivadas , Cerebelo/citologia , Glicoproteínas/genética , Ligantes , Proteínas do Tecido Nervoso/genética , Neurogênese , Neuroglia/citologia , Neurônios/citologia
15.
Sci Rep ; 8(1): 13275, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185803

RESUMO

The airway epithelium regulates responses to aeroallergens, acting as a physical and immunological barrier. In asthma, epithelial barrier function and the expression of adherens junction protein E-cadherin is compromised, but it is unknown whether this is cause or consequence of the disease. We hypothesized that airway epithelial loss of E-cadherin is a critical step in the development of manifestations of asthma. We generated a transgenic mouse model with conditional loss of E-cadherin in lung epithelial cells at birth and onwards. We observed normal lung development at the time of birth in mice lacking E-cadherin in the lung epithelium. However, E-cadherin deficiency led to progressive epithelial damage in mice growing into adulthood, as evidenced by airway epithelial denudation, decreased zonula occludens (ZO)-1 expression, loss of ciliated cells, and enlarged alveolar spaces. In addition, spontaneous goblet cell metaplasia with mucus production was observed. These epithelial changes were accompanied by elevated levels of the epithelial-derived chemokine CCL17, infiltration of eosinophils and dendritic cells, and mucus production. In conclusion, loss of E-cadherin induces features in the lung reminiscent of those observed in asthma, indicating that the disruption of E-cadherin-mediated cell-cell contacts may play a key role in the development of asthma manifestations.


Assuntos
Caderinas/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Junções Aderentes/metabolismo , Animais , Asma/metabolismo , Caderinas/genética , Caderinas/fisiologia , Quimiocina CCL17/metabolismo , Células Dendríticas/imunologia , Modelos Animais de Doenças , Eosinófilos/metabolismo , Células Epiteliais/metabolismo , Epitélio/metabolismo , Células Caliciformes/metabolismo , Pulmão/patologia , Metaplasia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Junções Íntimas/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
16.
Proc Natl Acad Sci U S A ; 115(33): 8388-8393, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30061390

RESUMO

The mechanosensory hair cells of the inner ear are required for hearing and balance and have a distinctive apical structure, the hair bundle, that converts mechanical stimuli into electrical signals. This structure comprises a single cilium, the kinocilium, lying adjacent to an ensemble of actin-based projections known as stereocilia. Hair bundle polarity depends on kinociliary protocadherin-15 (Pcdh15) localization. Protocadherin-15 is found only in hair-cell kinocilia, and is not localized to the primary cilia of adjacent supporting cells. Thus, Pcdh15 must be specifically targeted and trafficked into the hair-cell kinocilium. Here we show that kinocilial Pcdh15 trafficking relies on cell type-specific coupling to the generic intraflagellar transport (IFT) transport mechanism. We uncover a role for fibroblast growth factor receptor 1 (FGFR1) in loading Pcdh15 onto kinociliary transport particles in hair cells. We find that on activation, FGFR1 binds and phosphorylates Pcdh15. Moreover, we find a previously uncharacterized role for clathrin in coupling this kinocilia-specific cargo with the anterograde IFT-B complex through the adaptor, DAB2. Our results identify a modified ciliary transport pathway used for Pcdh15 transport into the cilium of the inner ear hair cell and coordinated by FGFR1 activity.


Assuntos
Caderinas/fisiologia , Flagelos/metabolismo , Células Ciliadas Auditivas Internas/metabolismo , Precursores de Proteínas/fisiologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Animais , Embrião de Galinha , Clatrina/fisiologia , Camundongos , Fosforilação , Transporte Proteico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise
17.
Int J Chron Obstruct Pulmon Dis ; 13: 2387-2398, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30127601

RESUMO

Introduction: COPD is a chronic inflammatory disease of lung. The inflammatory response in COPD is associated with neutrophils, macrophages, T lymphocytes, and bronchial epithelial cells, and occurs mainly in the small airway, leading to irreversible airflow limitation. Methods: In order to investigate the microRNA-mRNA interaction in the microenvironment of the COPD airway, we used next-generation sequencing and bioinformatics in this study. Results: We identified four genes with microRNA-mRNA interactions involved in COPD small-airway bronchial epithelial cells: NT5E, SDK1, TNS1, and PCDH7. Furthermore, miR6511a-5p-NT5E interaction was found to be involved in small-airway bronchial epithelial cells, large-airway bronchial epithelial cells, and alveolar macrophages. Conclusion: Our results showed that miR6511a-5p-NT5E interaction plays an important role in COPD, which might be associated with cell-cell contact, activation of leukocytes, activation of T lymphocytes, and cellular homeostasis. These findings provide new information for further investigations of the COPD microenvironment, and may help to develop new diagnostic or therapeutic strategies targeting the bronchial epithelium for COPD.


Assuntos
5'-Nucleotidase/genética , Caderinas/genética , Moléculas de Adesão Celular/genética , Biologia Computacional , Sequenciamento de Nucleotídeos em Larga Escala , Doença Pulmonar Obstrutiva Crônica/genética , Tensinas/genética , 5'-Nucleotidase/fisiologia , Brônquios , Caderinas/fisiologia , Moléculas de Adesão Celular/fisiologia , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/fisiologia , Perfilação da Expressão Gênica , Humanos , MicroRNAs/fisiologia , Mucosa Respiratória , Tensinas/fisiologia
18.
PLoS Comput Biol ; 14(8): e1006399, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30118477

RESUMO

The adherens junctions between epithelial cells involve a protein complex formed by E-cadherin, ß-catenin, α-catenin and F-actin. The stability of this complex was a puzzle for many years, since in vitro studies could reconstitute various stable subsets of the individual proteins, but never the entirety. The missing ingredient turned out to be mechanical tension: a recent experiment that applied physiological forces to the complex with an optical tweezer dramatically increased its lifetime, a phenomenon known as catch bonding. However, in the absence of a crystal structure for the full complex, the microscopic details of the catch bond mechanism remain mysterious. Building on structural clues that point to α-catenin as the force transducer, we present a quantitative theoretical model for how the catch bond arises, fully accounting for the experimental lifetime distributions. The underlying hypothesis is that force induces a rotational transition between two conformations of α-catenin, overcoming a significant energy barrier due to a network of salt bridges. This transition allosterically regulates the energies at the interface between α-catenin and F-actin. The model allows us to predict these energetic changes, as well as highlighting the importance of the salt bridge rotational barrier. By stabilizing one of the α-catenin states, this barrier could play a role in how the complex responds to additional in vivo binding partners like vinculin. Since significant conformational energy barriers are a common feature of other adhesion systems that exhibit catch bonds, our model can be adapted into a general theoretical framework for integrating structure and function in a variety of force-regulated protein complexes.


Assuntos
Junções Aderentes/fisiologia , Mecanotransdução Celular/fisiologia , Citoesqueleto de Actina/metabolismo , Actinas/fisiologia , Animais , Caderinas/fisiologia , Cateninas/fisiologia , Adesão Celular/fisiologia , Simulação por Computador , Células Epiteliais/metabolismo , Humanos , Modelos Teóricos , Ligação Proteica/fisiologia , Domínios Proteicos/fisiologia , Estresse Mecânico
19.
PLoS Genet ; 14(8): e1007609, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30118484

RESUMO

Cell polarity and correct mitotic spindle positioning are essential for the maintenance of a proper prostate epithelial architecture, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. However, whether and how these two epithelial attributes are connected in vivo is largely unknown. We herein report that conditional genetic deletion of E-cadherin, a key component of adherens junctions, in a mouse model results in loss of prostate luminal cell polarity and randomization of spindle orientations. Critically, E-cadherin ablation causes prostatic hyperplasia which progresses to invasive adenocarcinoma. Mechanistically, E-cadherin and the spindle positioning determinant LGN interacts with the PDZ domain of cell polarity protein SCRIB and form a ternary protein complex to bridge cell polarity and cell division orientation. These findings provide a novel mechanism by which E-cadherin acts an anchor to maintain prostate epithelial integrity and to prevent carcinogenesis in vivo.


Assuntos
Caderinas/fisiologia , Polaridade Celular , Próstata/citologia , Fuso Acromático/fisiologia , Animais , Caderinas/genética , Carcinogênese , Divisão Celular , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Epitélio , Deleção de Genes , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Knockout , Neoplasias da Próstata/patologia
20.
Lab Invest ; 98(11): 1364-1374, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29967341

RESUMO

Cadherin 11 (Cdh11), a member of the cadherin adhesion molecule family, is expressed in various regions of the brain as well as the head and ear. To gain further insights into the roles of Cdh11 in the development of the ear, we performed behavioral tests using Cdh11 knockout (KO) mice. KO mice showed reduced acoustic startle responses and increased thresholds for auditory brainstem responses, indicating moderate hearing loss. The auditory bulla volume and ratio of air-filled to non-air-filled space in the middle ear cavity were reduced in KO mice, potentially causing conductive hearing loss. Furthermore, residual mesenchymal and inflammatory cells were observed in the middle ear cavity of KO mice. Cdh11 was expressed in developing mesenchymal cells just before the start of cavitation, indicating that Cdh11 may be directly involved in middle ear cavitation. Since the auditory bulla is derived from the neural crest, the regulation of neural crest-derived cells by Cdh11 may be responsible for structural development. This mutant mouse may be a promising animal model for elucidating the causes of conductive hearing loss and otitis media.


Assuntos
Caderinas/fisiologia , Orelha Média/crescimento & desenvolvimento , Audição , Animais , Feminino , Masculino , Camundongos Knockout
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