RESUMO
The extracellular matrix (ECM) is composed of a mesh of proteins, proteoglycans, growth factors, and other secretory components. It constitutes the tumor microenvironment along with the endothelial cells, cancer-associated fibroblasts, adipocytes, and immune cells. The proteins of ECM can be functionally classified as adhesive proteins and matricellular proteins (MCP). In the tumor milieu, the ECM plays a major role in tumorigenesis and therapeutic resistance. The current review encompasses thrombospondins, osteonectin, osteopontin, tenascin C, periostin, the CCN family, laminin, biglycan, decorin, mimecan, and galectins. The matrix metalloproteinases (MMPs) are also discussed as they are an integral part of the ECM with versatile functions in the tumor stroma. In this review, the role of these proteins in tumor initiation, growth, invasion and metastasis have been highlighted, with emphasis on their contribution to tumor therapeutic resistance. Further, their potential as biomarkers and therapeutic targets based on existing evidence are discussed. Owing to the recent advancements in protein targeting, the possibility of agents to modulate MCPs in cancer as therapeutic options are discussed.
Assuntos
Biomarcadores Tumorais , Proteínas da Matriz Extracelular/fisiologia , Neoplasias/etiologia , Neoplasias/terapia , Moléculas de Adesão Celular/fisiologia , Proteínas da Matriz Extracelular/análise , Humanos , Metaloproteinases da Matriz/fisiologia , Osteonectina/análise , Osteonectina/fisiologia , Osteopontina/fisiologia , Tenascina/fisiologia , Trombospondina 1/fisiologia , Resultado do TratamentoRESUMO
BACKGROUND: Bacterial-mediated cancer immunotherapy (BCI) elicits a more robust initial immune response than conventional immunotherapy, but does not prevent tumor recurrence and metastasis. BCI is associated with recruitment of tumor-infiltrating neutrophils, which could suppress the therapeutic efficacy of this modality. Development endothelial locus 1 (Del-1), a potent inhibitor of neutrophil recruitment, antagonizes lymphocyte function-associated antigen-1 on the vascular endothelium. Here, we aimed to determine the effect of Del-1-secreting S.tâ³ppGpp on anti-tumor activity and tumor-infiltrating neutrophil recruitment in a mouse model of colon cancer. METHODS: We investigated the anti-cancer activity of Del-1-secreting engineered Salmonella (â³ppGpp S. Typhimurium) in the mice colon cancer models. RESULTS: In the present study, we identified that Del-1-secreting engineered Salmonella had more potent anti-cancer activity compared with normal S.tâ³ppGpp without Del-1 secretion. We postulated that Del-1 expression increased M1 macrophage recruitment to tumors by decreasing tumor-infiltrating neutrophils. This approach could enhance the anti-cancer effects of S.tâ³ppGpp. CONCLUSIONS: Collectively, the approach of using engineered bacteria that deliver Del-1 to block tumor-infiltrating neutrophil recruitment is a potential therapeutic approach.
Assuntos
Terapia Biológica/métodos , Proteínas de Ligação ao Cálcio/fisiologia , Moléculas de Adesão Celular/fisiologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Infiltração de Neutrófilos , Salmonella typhimurium , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Resultado do TratamentoRESUMO
Rationale: Angiogenesis and osteogenesis are highly coupled processes which are indispensable to bone repair. However, the underlying mechanism(s) remain elusive. To bridge the gap in understanding the coupling process is crucial to develop corresponding solutions to abnormal bone healing. Epidermal growth factor-like protein 6 (EGFL6) is an angiogenic factor specifically and distinctively up-regulated during osteoblast differentiation. In contrast with most currently known osteoblast-derived coupling factors, EGFL6 is highlighted with little or low expression in other cells and tissues. Methods: In this study, primary bone marrow mesenchymal stem cells (MSCs) and osteoblastic cell line (MC3T3-E1) were transduced with lentiviral silencing or overexpression constructs targeting EGFL6. Cells were induced by osteogenic medium, followed by the evaluation of mineralization as well as related gene and protein expression. Global and conditional knockout mice were established to examine the bone phenotype under physiological condition. Furthermore, bone defect models were created to investigate the outcome of bone repair in mice lacking EGFL6 expression. Results: We show that overexpression of EGFL6 markedly enhances osteogenic capacity in vitro by augmenting bone morphogenic protein (BMP)-Smad and MAPK signaling, whereas downregulation of EGFL6 diminishes osteoblastic mineralization. Interestingly, osteoblast differentiation was not affected by the exogenous addition of EGFL6 protein, thereby indicating that EGFL6 may regulate osteoblastic function in an intracrine manner. Mice with osteoblast-specific and global knockout of EGFL6 surprisingly exhibit a normal bone phenotype under physiological conditions. However, EGFL6-deficiency leads to compromised bone repair in a bone defect model which is characterized by decreased formation of type H vessels as well as osteoblast lineage cells. Conclusions: Together, these data demonstrate that EGFL6 serves as an essential regulator to couple osteogenesis to angiogenesis during bone repair.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Moléculas de Adesão Celular/metabolismo , Neovascularização Fisiológica/fisiologia , Osteogênese/fisiologia , Animais , Células da Medula Óssea/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Regeneração Óssea/fisiologia , Osso e Ossos/metabolismo , Proteínas de Ligação ao Cálcio/fisiologia , Moléculas de Adesão Celular/fisiologia , Diferenciação Celular/fisiologia , Linhagem Celular , Feminino , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/metabolismo , Cultura Primária de Células , Transdução de Sinais , Proteínas Smad/metabolismoRESUMO
The Nectin cell adhesion molecule (Nectin) family members are Ca2+independent immunoglobulinlike cellular adhesion molecules (including Nectins 14), involved in cell adhesion via homophilic/heterophilic interplay. In addition, the Nectin family plays a significant role in enhancing cellular viability and movement ability. In contrast to enrichment of Nectins 13 in normal tissues, Nectin4 is particularly overexpressed in a number of tumor types, including breast, lung, urothelial, colorectal, pancreatic and ovarian cancer. Moreover, the upregulation of Nectin4 is an independent biomarker for overall survival in numerous cancer types. A large number of studies have revealed that high expression of Nectin4 is closely related to tumor occurrence and development in various cancer types, but the manner in which Nectin4 protein contributes to the onset and development of these malignancies is yet unknown. The present review summarizes the molecular mechanisms and functions of Nectin4 protein in the biological processes and current advances with regard to its expression and regulation in various cancer types.
Assuntos
Moléculas de Adesão Celular/fisiologia , Neoplasias/etiologia , Anticorpos Monoclonais/farmacologia , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/química , Ensaios Clínicos como Assunto , Transição Epitelial-Mesenquimal , Humanos , Neoplasias/terapia , Neovascularização Patológica/etiologia , Terapia Viral Oncolítica , Transdução de Sinais/fisiologiaRESUMO
Trophoblast cell-surface antigen 2 (Trop 2) is a transmembrane glycoprotein that is highly expressed in various cancer types with relatively low or no baseline expression in most normal tissues. Its overexpression is associated with tumor growth and poor prognosis; Trop 2 is, therefore, an ideal therapeutic target for epithelial cancers. Several Trop 2 targeted therapeutics have recently been developed for the treatment of cancers, such as anti-Trop 2 antibodies and antibody-drug conjugates (ADCs), as well as Trop 2-specific cell therapy. In particular, the safety and clinical benefit of Trop 2-based ADCs have been demonstrated in clinical trials across multiple tumor types, including those with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and heavily pretreated non-small cell lung cancer. In this review, we elaborate on recent advances in Trop 2 targeted modalities and provide an overview of novel insights for future developments in this field.
Assuntos
Moléculas de Adesão Celular/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Antígenos de Neoplasias/química , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/fisiologia , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/fisiologia , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia AdotivaRESUMO
Pnn, a multiple functional protein, plays roles in embryonic development, cellular differentiation, tumorigenesis, and metastasis. In the past two decades, the functions of Pnn in regulating RNA alternative splicing, gene regulation, and cell-cell connection have been revealed. Although Pnn is originally identified as a desmosome-associated protein for linking desmosome and intermediated filament, emerging evidence implies that Pnn not only is a desmosome protein but also plays critical roles in the nucleus. To date, through cell biology investigation and the generation of animal models with genetic manipulation, the physiological role of Pnn has been characterized in the research fields of developmental biology, tumor biology, and neuroscience. Through proteomic and molecular biology studies, transcription regulators, splicing regulators, and cytoskeletal proteins were found to interact with Pnn. In addition, histopathological and biochemical evidence has pointed to an association of Pnn expression level with tumorigenesis and metastasis. A previous clinical study also demonstrated a correlation between a reduced expression of Pnn and human dementia. Besides, experimental studies showed a protective role of Pnn against ischemic stress in astrocytes. All indicated a variety of roles of Pnn in different cell types. In this review article, we introduced the role of Pnn in embryogenesis and pathogenesis as well as discussed its potential clinical application.
Assuntos
Carcinogênese/metabolismo , Moléculas de Adesão Celular/fisiologia , Proliferação de Células/fisiologia , Desenvolvimento Embrionário/fisiologia , Proteínas Nucleares/fisiologia , Animais , Carcinogênese/genética , Carcinogênese/patologia , HumanosRESUMO
Different body systems (epidermis, respiratory tract, cornea, oral cavity, and gastrointestinal tract) are in continuous direct contact with innocuous and/or potentially harmful external agents, exhibiting dynamic and highly selective interaction throughout the epithelia, which function as both a physical and chemical protective barrier. Resident immune cells in the epithelia are constantly challenged and must distinguish among antigens that must be either tolerated or those to which a response must be mounted for. When such a decision begins to take place in lymphoid foci and/or mucosa-associated lymphoid tissues, the epithelia network of immune surveillance actively dominates both oral and gastrointestinal compartments, which are thought to operate in the same immune continuum. However, anatomical variations clearly differentiate immune processes in both the mouth and gastrointestinal tract that demonstrate a wide array of independent immune responses. From single vs. multiple epithelia cell layers, widespread cell-to-cell junction types, microbial-associated recognition receptors, dendritic cell function as well as related signaling, the objective of this review is to specifically contrast the current knowledge of oral versus gut immune niches in the context of epithelia/lymphoid foci/MALT local immunity and systemic output. Related differences in 1) anatomy 2) cell-to-cell communication 3) antigen capture/processing/presentation 4) signaling in regulatory vs. proinflammatory responses and 5) systemic output consequences and its relations to disease pathogenesis are discussed.
Assuntos
Alostase , Homeostase , Imunidade nas Mucosas/imunologia , Vigilância Imunológica/imunologia , Mucosa Intestinal/imunologia , Mucosa Bucal/imunologia , Imunidade Adaptativa , Animais , Apresentação de Antígeno , Translocação Bacteriana/imunologia , Moléculas de Adesão Celular/fisiologia , Comunicação Celular , Células Dendríticas/imunologia , Disbiose/imunologia , Células Epiteliais/imunologia , Humanos , Inflamação , Junções Intercelulares/fisiologia , Mucosa Intestinal/citologia , Microbiota , Mucosa Bucal/citologia , Muco/fisiologia , Especificidade de Órgãos , Saliva/imunologia , Transdução de SinaisRESUMO
Matricellular proteins (MCPs) are defined as extracellular matrix (ECM) associated proteins that are important regulators and integrators of microenvironmental signals, contributing to the dynamic nature of ECM signalling. There is a growing understanding of the role of matricellular proteins in cellular processes governing tissue development as well as in disease pathogenesis. In this review, the expression and functions of different MP family members (periostin, CCNs, TSPs, SIBLINGs and others) are presented, specifically in relation to craniofacial development and the maintenance of orofacial tissues, including bone, gingiva, oral mucosa, palate and the dental pulp. As will be discussed, each MP family member has been shown to have non-redundant roles in development, tissue homeostasis, wound healing, pathology and tumorigenesis of orofacial and dental tissues.
Assuntos
Moléculas de Adesão Celular/fisiologia , Proteínas da Matriz Extracelular/fisiologia , Boca/crescimento & desenvolvimento , Osteonectina/fisiologia , Trombospondinas/fisiologia , Animais , Proteínas de Sinalização Intercelular CCN/fisiologia , Neoplasias de Cabeça e Pescoço/etiologia , Humanos , Boca/embriologia , Tenascina/fisiologia , CicatrizaçãoRESUMO
Mechanical forces control cell behavior, including cancer progression. Cells sense forces through actomyosin to activate YAP. However, the regulators of F-actin dynamics playing relevant roles during mechanostransduction in vitro and in vivo remain poorly characterized. Here we identify the Fascin1 F-actin bundling protein as a factor that sustains YAP activation in response to ECM mechanical cues. This is conserved in the mouse liver, where Fascin1 regulates YAP-dependent phenotypes, and in human cholangiocarcinoma cell lines. Moreover, this is relevant for liver tumorigenesis, because Fascin1 is required in the AKT/NICD cholangiocarcinogenesis model and it is sufficient, together with AKT, to induce cholangiocellular lesions in mice, recapitulating genetic YAP requirements. In support of these findings, Fascin1 expression in human intrahepatic cholangiocarcinomas strongly correlates with poor patient prognosis. We propose that Fascin1 represents a pro-oncogenic mechanism that can be exploited during intrahepatic cholangiocarcinoma development to overcome a mechanical tumor-suppressive environment.
Assuntos
Neoplasias dos Ductos Biliares/etiologia , Proteínas de Transporte/fisiologia , Proteínas de Ciclo Celular/fisiologia , Colangiocarcinoma/etiologia , Mecanotransdução Celular/fisiologia , Proteínas dos Microfilamentos/fisiologia , Fatores de Transcrição/fisiologia , Complexo 2-3 de Proteínas Relacionadas à Actina/fisiologia , Animais , Proteína de Capeamento de Actina CapZ/fisiologia , Moléculas de Adesão Celular/fisiologia , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Fosfoproteínas/fisiologiaRESUMO
Purpose: Circular RNAs (circRNAs) are essential regulators in tumorigenesis and development. In this study, we focused on the functions of circRNA muskelin 1 (circMKLN1) in retinoblastoma (RB) progression.Materials and Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) assay was conducted to determine the levels of circMKLN1, microRNA-425-5p (miR-425-5p) and programmed cell death 4 (PDCD4). The characteristic of circMKLN1 was analyzed using RNase R assay. Cell Counting Kit-8 (CCK-8) assay and colony formation assay were employed to explore cell proliferation ability. The transwell assay was utilized for cell migration and invasion. A Western blot assay was performed for protein levels. The dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to demonstrate the relationships among circMKLN1, miR-425-5p and PDCD4. Murine xenograft model assay was adopted to investigate the role of circMKLN1 in vivo.Results: CircMKLN1 was downregulated in RB tissues and cells. High levels of circMKLN1 were related to a favorable outcome of RB patients. CircMKLN1 was resistant to RNase R digestion and circMKLN1 overexpression repressed RB cell proliferation, migration and invasion in vitro. MiR-425-5p was identified as the target of circMKLN1 and miR-425-5p elevation reversed the effects of circMKLN1 overexpression on RB cell malignant behaviors. Furthermore, as the target gene of miR-425-5p, PDCD4 silencing could ameliorate the suppressive roles of circMKLN1 in RB cell growth and metastasis. Additionally, circMKLN1 overexpression hampered tumor growth in vivo.Conclusions: CircMKLN1 overexpression decelerated the progression of RB through sponging miR-425-5p and elevating PDCD4.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Moléculas de Adesão Celular/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , MicroRNAs/genética , RNA Circular/fisiologia , Proteínas de Ligação a RNA/genética , Neoplasias da Retina/fisiopatologia , Retinoblastoma/fisiopatologia , Animais , Western Blotting , Contagem de Células , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ensaio de Unidades Formadoras de Colônias , Progressão da Doença , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias da Retina/genética , Retinoblastoma/genética , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Measles virus (MeV), an enveloped RNA virus in the family Paramyxoviridae, is still an important cause of childhood morbidity and mortality worldwide. MeV usually causes acute febrile illness with skin rash, but in rare cases persists in the brain, causing a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE). The disease is fatal, and no effective therapy is currently available. Although transsynaptic cell-to-cell transmission is thought to account for MeV propagation in the brain, neurons do not express the known receptors for MeV. Recent studies have shown that hyperfusogenic changes in the MeV fusion (F) protein play a key role in MeV propagation in the brain. However, how such mutant viruses spread in neurons remains unexplained. Here, we show that cell adhesion molecule 1 (CADM1; also known as IGSF4A, Necl-2, and SynCAM1) and CADM2 (also known as IGSF4D, Necl-3, SynCAM2) are host factors that enable MeV to cause membrane fusion in cells lacking the known receptors and to spread between neurons. During enveloped virus entry, a cellular receptor generally interacts in trans with the attachment protein on the envelope. However, CADM1 and CADM2 interact in cis with the MeV attachment protein on the same cell membrane, causing the fusion protein triggering and membrane fusion. Knockdown of CADM1 and CADM2 inhibits syncytium formation and virus transmission between neurons that are both mediated by hyperfusogenic F proteins. Thus, our results unravel the molecular mechanism (receptor-mimicking cis-acting fusion triggering) by which MeV spreads transsynaptically between neurons, thereby causing SSPE. IMPORTANCE Measles virus (MeV), an enveloped RNA virus, is the causative agent of measles, which is still an important cause of childhood morbidity and mortality worldwide. Persistent MeV infection in the brain causes a fatal progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. However, how MeV spreads in neurons, which are mainly affected in SSPE, remains largely unknown. In this study, we demonstrate that cell adhesion molecule 1 (CADM1) and CADM2 are host factors enabling MeV spread between neurons. During enveloped virus entry, a cellular receptor generally interacts in trans with the attachment protein on the viral membrane (envelope). Remarkably, CADM1 and CADM2 interact in cis with the MeV attachment protein on the same membrane, triggering the fusion protein and causing membrane fusion, as viral receptors usually do in trans. Careful screening may lead to more examples of such "receptor-mimicking cis-acting fusion triggering" in other viruses.
Assuntos
Molécula 1 de Adesão Celular/fisiologia , Moléculas de Adesão Celular/fisiologia , Vírus do Sarampo/patogenicidade , Panencefalite Esclerosante Subaguda/virologia , Internalização do Vírus , Animais , Linhagem Celular , Chlorocebus aethiops , Células Gigantes/virologia , Humanos , Camundongos , Células Vero , Proteínas do Envelope Viral/metabolismo , Proteínas Virais de Fusão/metabolismoRESUMO
OBJECTIVE: Normal tooth eruption is closely related to relevant genes and the dynamic balance between osteoblasts and osteoclasts. If secretion of RANKL and OPG by osteoblasts is disordered, relevant gene deficiencies or mutations will result in serious tooth eruption disturbances, e.g., cleidocranial dysplasia (CCD). Thus, we examined changes in Runx2, RANKL, and OPG protein expression in MC3T3-E1 cells after silencing the periostin gene, thus, providing an experimental basis to study tooth eruption mechanisms. METHODS: Based on previous research, cells were divided into two groups according to the virus number: the contrast group (NC group; pFU-GW-016 PSC53349-1) and the experimental group (KD group; LVpFU-GW-016PSC66473-1). Cells were infected with the lentiviral vector (multiplicity of infectionâ¯= 100) and assessed by image cytometry 72â¯h after infection. After screening cells for the strongest gene silencing effect, Runx2, RANKL and OPG protein expression were detected by western blotting. RESULTS: Based on quantitative PCR, the periostin gene silencing efficiency in the KD group was over 90% (Pâ¯< 0.01). After periostin gene silencing, compared with the control group, Runx2 and RANKL expression in the KD group was reduced (Pâ¯< 0.01 and Pâ¯< 0.05, respectively), but OPG protein expression showed no significant change (Pâ¯> 0.05). The RANKL/OPG ratios in the KD group were lower than those in the NC group after periostin gene silencing (Pâ¯< 0.05). CONCLUSIONS: Silencing periostin may reduce the expression of Runx2, suggesting that there may be a synergistic relationship between periostin and Runx2 in their effects on osteoblast differentiation, while reducing RANKL expression obviously confirms that the NF-κB (nuclear factor κB) pathway plays an important role in this process and that periostin silencing changes the underlying tendency toward bone metabolism. This method could even provide an experimental basis for using exogenous periostin protein to treat some abnormal bone metabolism diseases, as it could be used as a supplement for the treatment of tooth eruption abnormalities caused by Runx2 gene deficiencies or mutations (CCD).
Assuntos
Moléculas de Adesão Celular , Osteoblastos , Ligante RANK , Animais , Moléculas de Adesão Celular/fisiologia , Diferenciação Celular , Subunidade alfa 1 de Fator de Ligação ao Core , Camundongos , Osteoclastos , Osteogênese , Osteoprotegerina/genética , Ligante RANK/genética , Erupção DentáriaAssuntos
Moléculas de Adesão Celular/antagonistas & inibidores , Oncologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Moléculas de Adesão Celular/fisiologia , Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/tendências , Humanos , Oncologia/métodos , Oncologia/tendências , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Inibidores de Proteínas Quinases/isolamento & purificação , Receptores Proteína Tirosina Quinases/fisiologiaRESUMO
TROP1 (EpCAM) and TROP2 are homologous cell surface proteins that are widely expressed, and often co-expressed, in developing and adult epithelia. Various functions have been ascribed to EpCAM and TROP2, but responsible mechanisms are incompletely characterized and functional equivalence has not been examined. Adult intestinal epithelial cells (IEC) express high levels of EpCAM, while TROP2 is not expressed. EpCAM deficiency causes congenital tufting enteropathy (CTE) in humans and a corresponding lethal condition in mice. We expressed TROP2 and EpCAM in the IEC of EpCAM-deficient mice utilizing a villin promoter to assess EpCAM and TROP2 function. Expression of EpCAM or TROP2 in the IEC of EpCAM knockout mice prevented CTE. TROP2 rescue (T2R) mice were smaller than controls, while EpCAM rescue (EpR) mice were not. Abnormalities were observed in the diameters and histology of T2R small intestine, and Paneth and stem cell markers were decreased. T2R mice also exhibited enlarged mesenteric lymph nodes, enhanced permeability to 4 kDa FITC-dextran and increased sensitivity to detergent-induced colitis, consistent with compromised barrier function. Studies of IEC organoids and spheroids revealed that stem cell function was also compromised in T2R mice. We conclude that EpCAM and TROP2 exhibit functional redundancy, but they are not equivalent.
Assuntos
Antígenos de Neoplasias/fisiologia , Moléculas de Adesão Celular/fisiologia , Diarreia Infantil/genética , Molécula de Adesão da Célula Epitelial/fisiologia , Células Epiteliais/metabolismo , Síndromes de Malabsorção/genética , Animais , Células HEK293 , Humanos , Mucosa Intestinal/citologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras GenéticasRESUMO
Macrolide antibiotics exert antiinflammatory effects; however, little is known regarding their immunomodulatory mechanisms. In this study, using 2 distinct mouse models of mucosal inflammatory disease (LPS-induced acute lung injury and ligature-induced periodontitis), we demonstrated that the antiinflammatory action of erythromycin (ERM) is mediated through upregulation of the secreted homeostatic protein developmental endothelial locus-1 (DEL-1). Consistent with the anti-neutrophil recruitment action of endothelial cell-derived DEL-1, ERM inhibited neutrophil infiltration in the lungs and the periodontium in a DEL-1-dependent manner. Whereas ERM (but not other antibiotics, such as josamycin and penicillin) protected against lethal pulmonary inflammation and inflammatory periodontal bone loss, these protective effects of ERM were abolished in Del1-deficient mice. By interacting with the growth hormone secretagogue receptor and activating JAK2 in human lung microvascular endothelial cells, ERM induced DEL-1 transcription that was mediated by MAPK p38 and was CCAAT/enhancer binding protein-ß dependent. Moreover, ERM reversed IL-17-induced inhibition of DEL-1 transcription, in a manner that was dependent not only on JAK2 but also on PI3K/AKT signaling. Because DEL-1 levels are severely reduced in inflammatory conditions and with aging, the ability of ERM to upregulate DEL-1 may lead to a novel approach for the treatment of inflammatory and aging-related diseases.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Proteínas de Ligação ao Cálcio/fisiologia , Moléculas de Adesão Celular/fisiologia , Eritromicina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Periodontite/tratamento farmacológico , Pneumonia/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Fármacos Gastrointestinais/farmacologia , Interleucina-17/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/patologia , Periodontite/etiologia , Periodontite/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Pneumonia/etiologia , Pneumonia/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Microgravity induces a number of significant physiological changes in the cardiovascular, nervous, immune systems, as well as the bone tissue of astronauts. Changes in cell adhesion properties are one aspect affected during long-term spaceflights in mammalian cells. Cellular adhesion behaviors can be divided into cell-cell and cell-matrix adhesion. These behaviors trigger cell-cell recognition, conjugation, migration, cytoskeletal rearrangement, and signal transduction. Cellular adhesion molecule (CAM) is a general term for macromolecules that mediate the contact and binding between cells or between cells and the extracellular matrix (ECM). In this review, we summarize the four major classes of adhesion molecules that regulate cell adhesion, including integrins, immunoglobulin superfamily (Ig-SF), cadherins, and selectin. Moreover, we discuss the effects of spaceflight and simulated microgravity on the adhesion of endothelial cells, immune cells, tumor cells, stem cells, osteoblasts, muscle cells, and other types of cells. Further studies on the effects of microgravity on cell adhesion and the corresponding physiological behaviors may help increase the safety and improve the health of astronauts in space.
Assuntos
Adesão Celular , Voo Espacial , Simulação de Ausência de Peso , Animais , Astronautas , Moléculas de Adesão Celular/classificação , Moléculas de Adesão Celular/fisiologia , Citoesqueleto/ultraestrutura , Células Endoteliais/citologia , Matriz Extracelular/metabolismo , Humanos , Sistema Imunitário/citologia , Camundongos , Células Musculares/citologia , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/citologia , Especificidade de Órgãos , Osteoblastos/citologia , Ratos , Células-Tronco/citologiaRESUMO
TIM-3 has been considered as a target in cancer immunotherapy. In T cells, inhibitory as well as activating functions have been ascribed to this molecule. Its role may therefore depend on the state of T cells and on the presence of interaction partners capable to perform functional pairing. Carcinoembryonic antigen-related cell adhesion molecule (CEACAM1) has been proposed to bind TIM-3 and to regulate its function. Using a T cell reporter platform we confirmed CEACAM1-mediated inhibition, but CEACAM1 did not functionally engage TIM-3. TIM-3 and CEACAM1 coexpression was limited to a small subset of activated T cells. Moreover, results obtained in extensive binding studies were not in support of an interaction between TIM-3 and CEACAM1. Cytoplasmic sequences derived from TIM-3 induced inhibitory signaling in our human T cell reporter system. Our results indicate that TIM-3 functions are independent of CEACAM1 and that this receptor has the capability to promote inhibitory signaling pathways in human T cells.
Assuntos
Antígenos CD/fisiologia , Moléculas de Adesão Celular/fisiologia , Receptor Celular 2 do Vírus da Hepatite A/fisiologia , Transferência Ressonante de Energia de Fluorescência , Células HEK293 , Receptor Celular 2 do Vírus da Hepatite A/análise , Humanos , Células Jurkat , Ativação Linfocitária , Transdução de Sinais/fisiologia , Linfócitos T/imunologiaRESUMO
This study was performed to investigate the role of PTK7 in esophageal squamous cell carcinoma (ESCC) stem-like cells (CSCs). PTK7 expression in ESCCs identified by RT-qPCR, and CSC-like cells were isolated from populations of NEC and TE-1 cells. The CSC-like cells were verified by flow cytometric analyses performed using CD34 and CD133 antibodies, and RT-qPCR and western blot assays were used to examine the self-renewal capability of CSC-like cells. CSC-like cells treated with PTK7 siRNA or a P53-specific inhibitor (PFTα) were analyzed for their sphere formation capacity and their apoptosis and migration/invasion capabilities by sphere formation, flow cytometry, and transwell assay, respectively. Their levels of P53, MKK3, and cleaved caspase 3 expression were examined by western blot analysis. Our results revealed that a majority of the isolated CSC-like cells were CD34+/CD133+ double positive cells. Nango, Sox2, and OCT4 were dramatically increased in the separated CSC-like cells, which had the pluripotency and self-renewal properties of stem cells. Additional, PTK7 was dramatically upregulated in the ESCC tissues and CSC-like cells. An investigation of the function of CSC-like cells revealed that knockdown of PTK7 reduced their sphere formation, promoted apoptosis, and suppressed their migration and invasion abilities, all of which could be significantly reversed by PFTα. Mechanistic studies showed that PFTα could attenuate the upregulation of P53, MKK3, and cleaved caspase 3 expression that was induced by PTK7 knockdown in CSC-like cells. PTK7 increased the malignant behaviors of CSC-like cells derived from ESCC cells by regulating p53. Therefore, this study suggests PTK7 as an underlying target for therapy against ESCC.
Assuntos
Carcinoma de Células Escamosas/patologia , Moléculas de Adesão Celular/fisiologia , Neoplasias Esofágicas/patologia , Células-Tronco Neoplásicas/patologia , Receptores Proteína Tirosina Quinases/fisiologia , Linhagem Celular Tumoral , HumanosRESUMO
BACKGROUND: The matricellular protein periostin has been associated with CKD progression in animal models and human biopsy specimens. Periostin functions by interacting with extracellular matrix components to drive collagen fibrillogenesis and remodeling or by signaling through cell-surface integrin receptors to promote cell adhesion, migration, and proliferation. However, its role in AKI is unknown. METHODS: We used mice with conditional tubule-specific overexpression of periostin or knockout mice lacking periostin expression in the renal ischemia-reperfusion injury model, and primary cultures of isolated tubular cells in a hypoxia-reoxygenation model. RESULTS: Tubular epithelial cells showed strong production of periostin during the repair phase of ischemia reperfusion. Periostin overexpression protected mice from renal injury compared with controls, whereas knockout mice showed increased tubular injury and deteriorated renal function. Periostin interacted with its receptor, integrin-ß1, to inhibit tubular cell cycle arrest and apoptosis in in vivo and in vitro models. After ischemia-reperfusion injury, periostin-overexpressing mice exhibited diminished expression of proinflammatory molecules and had more F4/80+ macrophages compared with knockout mice. Macrophages from periostin-overexpressing mice showed increased proliferation and expression of proregenerative factors after ischemia-reperfusion injury, whereas knockout mice exhibited the opposite. Coculturing a macrophage cell line with hypoxia-treated primary tubules overexpressing periostin, or treating such macrophages with recombinant periostin, directly induced macrophage proliferation and expression of proregenerative molecules. CONCLUSIONS: In contrast to the detrimental role of periostin in CKD, we discovered a protective role of periostin in AKI. Our findings suggest periostin may be a novel and important mediator of mechanisms controlling renal repair after AKI.
Assuntos
Injúria Renal Aguda , Moléculas de Adesão Celular/fisiologia , Proliferação de Células , Macrófagos/fisiologia , Injúria Renal Aguda/etiologia , Animais , Modelos Animais de Doenças , Rim/irrigação sanguínea , Masculino , Camundongos , Camundongos Knockout , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologiaRESUMO
DC-SIGN is previously focused on its physiologic and pathophysiologic roles in immune cells. Little is known about whether DC-SIGN is expressed in malignant epithelial cells and how DC-SIGN participates in tumor progression. Here we showed that DC-SIGN expression was increased in metastatic colorectal cancer (CRC) cell lines and patient tissues. The overall survival in CRC patients with positive DC-SIGN was remarkably reduced. Gain of DC-SIGN function facilitated the CRC metastases both in vitro and in vivo, and this effect was reversed by miR-185. DC-SIGN and Lyn interacted physically, and Lyn maintained the stability of DC-SIGN in cells. DC-SIGN activation recruited Lyn and p85 to form the DC-SIGN-Lyn-p85 complex, which promoted CRC metastasis by increasing PI3K/Akt/ß-catenin signaling in tyrosine kinase Lyn-dependent manner. Furthermore, activation of DC-SIGN promoted the transcription of MMP-9 and VEGF by increasing PI3K/Akt/ß-catenin signaling, and induced TCF1/LEF1-mediated suppression of miR-185. Our findings reveal the presence of the DC-SIGN-TCF1/LEF1-miR-185 loop in cancer cells with metastatic traits, implying that it may represent a new pathogenic mechanism of CRC metastasis. This character of the loop promises to provide new targets for blocking CRC invasive and metastatic activity.