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1.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34521767

RESUMO

Early stages of colorectal cancer (CRC) development are characterized by a complex rewiring of transcriptional networks resulting in changes in the expression of multiple genes. Here, we demonstrate that the deletion of a poorly studied tetraspanin protein Tspan6 in Apcmin/+ mice, a well-established model for premalignant CRC, resulted in increased incidence of adenoma formation and tumor size. We demonstrate that the effect of Tspan6 deletion results in the activation of EGF-dependent signaling pathways through increased production of the transmembrane form of TGF-α (tmTGF-α) associated with extracellular vesicles. This pathway is modulated by an adaptor protein syntenin-1, which physically links Tspan6 and tmTGF-α. In support of this, the expression of Tspan6 is frequently decreased or lost in CRC, and this correlates with poor survival. Furthermore, the analysis of samples from the epidermal growth factor receptor (EGFR)-targeting clinical trial (COIN trial) has shown that the expression of Tspan6 in CRC correlated with better patient responses to EGFR-targeted therapy involving Cetuximab. Importantly, Tspan6-positive patients with tumors in the proximal colon (right-sided) and those with KRAS mutations had a better response to Cetuximab than the patients that expressed low Tspan6 levels. These results identify Tspan6 as a regulator of CRC development and a potential predictive marker for EGFR-targeted therapies in CRC beyond RAS pathway mutations.


Assuntos
Biomarcadores Tumorais/metabolismo , Cetuximab/farmacologia , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Tetraspaninas/metabolismo , Tetraspaninas/fisiologia , Animais , Antineoplásicos Imunológicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prognóstico , Taxa de Sobrevida , Tetraspaninas/genética , Células Tumorais Cultivadas
2.
Biomolecules ; 11(8)2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34439793

RESUMO

The histamine H4 receptor (H4R) is a G protein-coupled receptor that is predominantly expressed on immune cells and considered to be an important drug target for various inflammatory disorders. Like most GPCRs, the H4R activates G proteins and recruits ß-arrestins upon phosphorylation by GPCR kinases to induce cellular signaling in response to agonist stimulation. However, in the last decade, novel GPCR-interacting proteins have been identified that may regulate GPCR functioning. In this study, a split-ubiquitin membrane yeast two-hybrid assay was used to identify H4R interactors in a Jurkat T cell line cDNA library. Forty-three novel H4R interactors were identified, of which 17 have also been previously observed in MYTH screens to interact with other GPCR subtypes. The interaction of H4R with the tetraspanin TSPAN4 was confirmed in transfected cells using bioluminescence resonance energy transfer, bimolecular fluorescence complementation, and co-immunoprecipitation. Histamine stimulation reduced the interaction between H4R and TSPAN4, but TSPAN4 did not affect H4R-mediated G protein signaling. Nonetheless, the identification of novel GPCR interactors by MYTH is a starting point to further investigate the regulation of GPCR signaling.


Assuntos
Receptores Histamínicos H4/metabolismo , Tetraspaninas/metabolismo , Técnicas de Transferência de Energia por Ressonância de Bioluminescência , Expressão Gênica , Biblioteca Gênica , Células HEK293 , Histamina/metabolismo , Histamina/farmacologia , Humanos , Células Jurkat , Fosforilação/efeitos dos fármacos , Ligação Proteica , Mapeamento de Interação de Proteínas , Receptores Histamínicos H4/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Transdução de Sinais , Tetraspaninas/genética , Transgenes , Técnicas do Sistema de Duplo-Híbrido
3.
Theranostics ; 11(16): 8092-8111, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335982

RESUMO

Active c-Src non-receptor tyrosine kinase localizes to the plasma membrane via N-terminal lipid modification. Membranous c-Src causes cancer initiation and progression. Even though transmembrane 4 L six family member 5 (TM4SF5), a tetraspan(in), can be involved in this mechanism, the molecular and structural influence of TM4SF5 on c-Src remains unknown. Methods: Here, we investigated molecular and structural details by which TM4SF5 regulated c-Src devoid of its N-terminus and how cell-penetrating peptides were able to interrupt c-Src activation via interference of c-Src-TM4SF5 interaction in hepatocellular carcinoma models. Results: The TM4SF5 C-terminus efficiently bound the c-Src SH1 kinase domain, efficiently to the inactively-closed form. The complex involved protein tyrosine phosphatase 1B able to dephosphorylate Tyr530. The c-Src SH1 domain alone, even in a closed form, bound TM4SF5 to cause c-Src Tyr419 and FAK Y861 phosphorylation. Homology modeling and molecular dynamics simulation studies predicted the directly interfacing residues, which were further validated by mutational studies. Cell penetration of TM4SF5 C-terminal peptides blocked the interaction of TM4SF5 with c-Src and prevented c-Src-dependent tumor initiation and progression in vivo. Conclusions: Collectively, these data demonstrate that binding of the TM4SF5 C-terminus to the kinase domain of inactive c-Src leads to its activation. Because this binding can be abolished by cell-penetrating peptides containing the TM4SF5 C-terminus, targeting this direct interaction may be an effective strategy for developing therapeutics that block the development and progression of hepatocellular carcinoma.


Assuntos
Proteína Tirosina Quinase CSK/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Membrana/metabolismo , Proteína Tirosina Quinase CSK/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Genes src/genética , Genes src/fisiologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Peptídeos/metabolismo , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Tetraspaninas/genética , Tetraspaninas/metabolismo
4.
J Cell Biol ; 220(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34132745

RESUMO

Photoreceptors rely on distinct membrane compartments to support their specialized function. Unlike protein localization, identification of critical differences in membrane content has not yet been expanded to lipids, due to the difficulty of isolating domain-specific samples. We have overcome this by using SMA to coimmunopurify membrane proteins and their native lipids from two regions of photoreceptor ROS disks. Each sample's copurified lipids were subjected to untargeted lipidomic and fatty acid analysis. Extensive differences between center (rhodopsin) and rim (ABCA4 and PRPH2/ROM1) samples included a lower PC to PE ratio and increased LC- and VLC-PUFAs in the center relative to the rim region, which was enriched in shorter, saturated FAs. The comparatively few differences between the two rim samples likely reflect specific protein-lipid interactions. High-resolution profiling of the ROS disk lipid composition gives new insights into how intricate membrane structure and protein activity are balanced within the ROS, and provides a model for future studies of other complex cellular structures.


Assuntos
Membrana Celular/metabolismo , Proteínas do Olho/metabolismo , Lipídeos de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Oxirredutases do Álcool/genética , Oxirredutases do Álcool/metabolismo , Animais , Bovinos , Membrana Celular/ultraestrutura , Proteínas do Olho/imunologia , Lipidômica , Proteínas de Membrana/imunologia , Camundongos Endogâmicos BALB C , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Nanotecnologia , Periferinas/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/ultraestrutura , Rodopsina/metabolismo , Anticorpos de Domínio Único/imunologia , Tetraspaninas/metabolismo
5.
Int J Biochem Cell Biol ; 137: 106029, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34174403

RESUMO

Acute myeloid leukemia (AML) is characterized by the disruption of myeloid differentiation and accumulation of blast cells in the bone marrow. While AML patients respond favorably to induction chemotherapy, long-term outcomes remain poor due to a high rate of chemoresistance. Advances with targeted therapies, which can be used in combination with conventional chemotherapy, have expanded therapeutic options for patients. However, remission is often short-lived and followed by disease relapse and drug resistance. Therefore, there is a substantial need to improve treatment options by identifying novel molecular and cellular targets that regulate AML chemosensitivity. Membrane scaffolds such as the tetraspanin family of proteins often serve as signaling mediators, translating extracellular signaling cues into intracellular signaling cascades. In this review, we discuss the conventional and targeted treatment strategies for AML and review chemoresistance mechanisms with a focus on the tetraspanin family of membrane scaffold proteins.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Tetraspaninas/metabolismo , Animais , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Tetraspaninas/genética
6.
Int J Mol Sci ; 22(9)2021 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-34065085

RESUMO

The role and prognostic value of tetraspanins (TSPANs) in vulvar squamous cell carcinoma (VSCC) remain poorly understood. We sought to primarily determine, at both the molecular and tissue level, the expression profile of the TSPANs CD9, CD63, CD81, and CD82 in archived VSCC samples (n = 117) and further investigate their clinical relevance as prognostic markers. Our studies led us to identify CD63 as the most highly expressed TSPAN, at the gene and protein levels. Multicomparison studies also revealed that the expression of CD9 was associated with tumor size, whereas CD63 upregulation was associated with histological diagnosis and vascular invasion. Moreover, low expression of CD81 and CD82 was associated with worse prognosis. To determine the role of TSPANs in VSCC at the cellular level, we assessed the mRNA levels of CD63 and CD82 in established metastatic (SW962) and non-metastatic (SW954) VSCC human cell lines. CD82 was found to be downregulated in SW962 cells, thus supporting its metastasis suppressor role. However, CD63 was significantly upregulated in both cell lines. Silencing of CD63 by siRNA led to a significant decrease in proliferation of both SW954 and SW962. Furthermore, in SW962 particularly, CD63-siRNA also remarkably inhibited cell migration. Altogether, our data suggest that the differential expression of TSPANs represents an important feature for prognosis of VSCC patients and indicates that CD63 and CD82 are likely potential therapeutic targets in VSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Regulação Neoplásica da Expressão Gênica , Tetraspaninas/genética , Transcriptoma , Neoplasias Vulvares/genética , Neoplasias Vulvares/mortalidade , Adulto , Idoso , Carcinoma de Células Escamosas/diagnóstico , Suscetibilidade a Doenças , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Tetraspaninas/metabolismo , Neoplasias Vulvares/patologia
7.
Comput Math Methods Med ; 2021: 6651764, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33680068

RESUMO

Some related reports indicate that the outer retinal membrane protein 1 (ROM1) functions importantly in the regulation of the biological process of tumor. Nevertheless, studies towards the role of ROM1 in lung cancer are few. Here, our data demonstrated that ROM1 displayed a relation with lung cancer tumorigenesis and development. In the Tumor Genome Atlas (TCGA) cohort, reduced ROM1 level was observed in lung cancer tissues, instead of normal tissues. After bioinformatics analysis, the data revealed that ROM1 level was associated with the tumor stage. Additional results indicated that highly expressed ROM1 exhibited a positive correlation with the overall survival rate, and ROM1 was probably a promising prognostic biomarker of lung cancer. Additionally, our results indicated that knocking out ROM1 could promote cell proliferation, migration, and invasion. Our data conclusively demonstrated that ROM1 modulated lung cancer tumorigenesis and development, as a prognosis and treatment biomarker.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas do Olho/metabolismo , Neoplasias Pulmonares/metabolismo , Tetraspaninas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Biologia Computacional , Bases de Dados Genéticas , Progressão da Doença , Proteínas do Olho/antagonistas & inibidores , Proteínas do Olho/genética , Técnicas de Inativação de Genes , Ontologia Genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Invasividade Neoplásica/genética , Prognóstico , Tetraspaninas/antagonistas & inibidores , Tetraspaninas/genética , Transcriptoma , Proteínas Supressoras de Tumor/genética
8.
Nat Commun ; 12(1): 1453, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674603

RESUMO

A major roadblock prohibiting effective cellular immunotherapy of pancreatic ductal adenocarcinoma (PDAC) is the lack of suitable tumor-specific antigens. To address this challenge, here we combine flow cytometry screenings, bioinformatic expression analyses and a cyclic immunofluorescence platform. We identify CLA, CD66c, CD318 and TSPAN8 as target candidates among 371 antigens and generate 32 CARs specific for these molecules. CAR T cell activity is evaluated in vitro based on target cell lysis, T cell activation and cytokine release. Promising constructs are evaluated in vivo. CAR T cells specific for CD66c, CD318 and TSPAN8 demonstrate efficacies ranging from stabilized disease to complete tumor eradication with CD318 followed by TSPAN8 being the most promising candidates for clinical translation based on functionality and predicted safety profiles. This study reveals potential target candidates for CAR T cell based immunotherapy of PDAC together with a functional set of CAR constructs specific for these molecules.


Assuntos
Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/metabolismo , Imunoterapia/métodos , Neoplasias Pancreáticas/metabolismo , Tetraspaninas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/terapia , Animais , Antígenos de Neoplasias/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/terapia , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Citocinas/metabolismo , Proteínas Ligadas por GPI/metabolismo , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Fatores Imunológicos , Ativação Linfocitária , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Linfócitos T/imunologia , Tetraspaninas/genética
9.
Clin Hemorheol Microcirc ; 78(1): 69-81, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33523043

RESUMO

PURPOSE: Acute myeloid leukemia (AML) is a type of hematologic malignancy. This study was attempt to explore the effect of long noncoding RNA GAS6 antisense RNA1 (GAS6-AS1) on pediatric AML and the regulation mechanisms. METHODS: GAS6-AS1, microRNA-370-3p (miR-370-3p), and Tetraspanin3 (TSPAN3) expression in bone marrow (BM) tissues and cells was determined by qRT-PCR. The correlation between GAS6-AS1 and clinicopathological features of pediatric patients with AML was assessed. In vitro, viability and migration and invasion of AML cells were evaluated via MTT and transwell assays, respectively. Interactions among GAS6-AS1, miR-370-3p, and TSPAN3 were revealed by dual-luciferase reporter assays. Western blot was applied to confirm the protein expression of TSPAN3. RESULTS: GAS6-AS1 and TSPAN3 expression was elevated in BM tissues of pediatric patients with AML and AML cells, but miR-370-3p expression was reduced. GAS6-AS1 expression was positively related to French-American-British (FAB) classification in pediatric patients with AML. In vitro, GAS6-AS1 deficiency restrained the viability, migration, and invasion of AML cells. Additionally, GAS6-AS1 mediated miR-370-3p expression indeed and TSPAN3 was identified as a target of miR-370-3p. Furthermore, miR-370-3p overexpression repressed the protein expression of TSPAN3. The feedback experiments demonstrated that miR-370-3p inhibition or TSPAN3 overexpression mitigated the suppressive effect of sh-GAS6-AS1 on the tumorigenesis of AML cells. CONCLUSION: GAS6-AS1 silencing restrained AML cell viability, migration, and invasion by targeting miR-370-3p/TSPAN3 axis, affording a novel therapeutic target for pediatric AML.


Assuntos
Carcinogênese/genética , Leucemia Mieloide Aguda/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Tetraspaninas/metabolismo , Proliferação de Células , Humanos , Leucemia Mieloide Aguda/patologia , RNA Longo não Codificante/genética , Tetraspaninas/genética
10.
Nat Plants ; 7(3): 342-352, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33633358

RESUMO

Plants use extracellular vesicles (EVs) to transport small RNAs (sRNAs) into their fungal pathogens and silence fungal virulence-related genes through a phenomenon called 'cross-kingdom RNAi'. It remains unknown, however, how sRNAs are selectively loaded into EVs. Here, we identified several RNA-binding proteins in Arabidopsis, including Argonaute 1 (AGO1), RNA helicases (RHs) and annexins (ANNs), which are secreted by exosome-like EVs. AGO1, RH11 and RH37 selectively bind to EV-enriched sRNAs but not to non-EV-associated sRNAs, suggesting that they contribute to the selective loading of sRNAs into EVs. Conversely, ANN1 and ANN2 bind to sRNAs non-specifically. The ago1, rh11 rh37 and ann1 ann2 mutants showed reduced secretion of sRNAs in EVs, demonstrating that these RNA-binding proteins play an important role in sRNA loading and/or stabilization in EVs. Furthermore, rh11 rh37 and ann1 ann2 showed increased susceptibility to Botrytis cinerea, suggesting that RH11, RH37, ANN1 and ANN2 positively regulate plant immunity against B. cinerea.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Vesículas Extracelulares/metabolismo , RNA de Plantas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Anexinas/metabolismo , Arabidopsis/genética , Arabidopsis/imunologia , Proteínas Argonauta/metabolismo , Botrytis , RNA Helicases DEAD-box/metabolismo , Doenças das Plantas/genética , Doenças das Plantas/imunologia , Proteoma , RNA Interferente Pequeno , Tetraspaninas/metabolismo
11.
J Virol ; 95(6)2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33361424

RESUMO

Extracellular vesicles (EVs) are released by all types of cells as a means of intercellular communication. Their significance lies in the fact that they can alter recipient cell functions, despite their limited capacity for cargo. We have previously demonstrated that herpes simplex virus 1 (HSV-1) infection influences the cargo and functions of EVs released by infected cells and that these EVs negatively impact a subsequent HSV-1 infection. In the present study, we have implemented cutting-edge technologies to further characterize EVs released during HSV-1 infection. We identified distinct EV populations that were separable through a gradient approach. One population was positive for the tetraspanin CD63 and was distinct from EVs carrying components of the endosomal sorting complexes required for transport (ESCRT). Nanoparticle tracking analysis (NTA) combined with protein analysis indicated that the production of CD63+ EVs was selectively induced upon HSV-1 infection. The ExoView platform supported these data and suggested that the amount of CD63 per vesicle is larger upon infection. This platform also identified EV populations positive for other tetraspanins, including CD81 and CD9, whose abundance decreased upon HSV-1 infection. The stimulator of interferon genes (STING) was found in CD63+ EVs released during HSV-1 infection, while viral components were found in ESCRT+ EVs. Functional characterization of these EVs demonstrated that they have opposite effects on the infection, but the dominant effect was negative. Overall, we have identified the dominant population of EVs, and other EV populations produced during HSV-1 infection, and we have provided information about potential roles.IMPORTANCE Extracellular vesicles mediate cell-to-cell communication and convey messages important for cell homeostasis. Pathways of EV biogenesis are often hijacked by pathogens to facilitate their dissemination and to establish a favorable microenvironment for the infection. We have previously shown that HSV-1 infection alters the cargo and functions of the released EVs, which negatively impact the infection. We have built upon our previous findings by developing procedures to separate EV populations from HSV-1-infected cells. We identified the major population of EVs released during infection, which carries the DNA sensor STING and has an antiviral effect. We also identified an EV population that carries selected viral proteins and has a proviral role. This is the first study to characterize EV populations during infection. These data indicate that the complex interactions between the virus and the host are extended to the extracellular environment and could impact HSV-1 dissemination and persistence in the host.


Assuntos
Vesículas Extracelulares/fisiologia , Herpesvirus Humano 1/fisiologia , Antivirais/metabolismo , Linhagem Celular , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Exocitose , Vesículas Extracelulares/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Proteínas de Membrana/metabolismo , Tetraspanina 30/metabolismo , Tetraspaninas/metabolismo , Proteínas Virais/metabolismo
13.
Cells ; 9(12)2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33302515

RESUMO

Epidermal growth factor receptor (EGFR) takes centre stage in carcinogenesis throughout its entire cellular trafficking odyssey. When loaded in extracellular vesicles (EVs), EGFR is one of the key proteins involved in the transfer of information between parental cancer and bystander cells in the tumour microenvironment. To hijack EVs, EGFR needs to play multiple signalling roles in the life cycle of EVs. The receptor is involved in the biogenesis of specific EV subpopulations, it signals as an active cargo, and it can influence the uptake of EVs by recipient cells. EGFR regulates its own inclusion in EVs through feedback loops during disease progression and in response to challenges such as hypoxia, epithelial-to-mesenchymal transition and drugs. Here, we highlight how the spatiotemporal rules that regulate EGFR intracellular function intersect with and influence different EV biogenesis pathways and discuss key regulatory features and interactions of this interplay. We also elaborate on outstanding questions relating to EGFR-driven EV biogenesis and available methods to explore them. This mechanistic understanding will be key to unravelling the functional consequences of direct anti-EGFR targeted and indirect EGFR-impacting cancer therapies on the secretion of pro-tumoural EVs and on their effects on drug resistance and microenvironment subversion.


Assuntos
Vesículas Extracelulares/metabolismo , Neoplasias/metabolismo , Progressão da Doença , Endocitose , Transição Epitelial-Mesenquimal , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Neoplasias/patologia , Transdução de Sinais , Tetraspaninas/metabolismo , Microambiente Tumoral
14.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333768

RESUMO

CD37 is a tetraspanin expressed prominently on the surface of B cells. It is an attractive molecular target exploited in the immunotherapy of B cell-derived lymphomas and leukemia. Currently, several monoclonal antibodies targeting CD37 as well as chimeric antigen receptor-based immunotherapies are being developed and investigated in clinical trials. Given the unique role of CD37 in the biology of B cells, it seems that CD37 constitutes more than a docking point for monoclonal antibodies, and targeting this molecule may provide additional benefit to relapsed or refractory patients. In this review, we aimed to provide an extensive overview of the function of CD37 in B cell malignancies, providing a comprehensive view of recent therapeutic advances targeting CD37 and delineating future perspectives.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos B/metabolismo , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/imunologia , Linfoma de Células B/imunologia , Tetraspaninas/imunologia , Tetraspaninas/metabolismo , Linfócitos B/imunologia , Linfócitos B/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo
15.
Int J Mol Sci ; 21(24)2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33316880

RESUMO

Stem cells for regenerative medicine purposes offer therapeutic benefits, but disadvantages are still ill defined. The benefit of stem cells may be attributed to their secretion of growth factors (GFs), cytokines (CKs), and extracellular vesicles (EVs), including exosomes. We present a novel cell-free stem cell-derived extract (CCM), formulated from human progenitor endothelial stem cells (hPESCs), characterized for biologically active factors using ELISA, nanoparticle tracking analysis and single particle interferometric reflectance imaging sensing. The effect on fibroblast proliferation and ability to induce stem cell migration was analyzed using Alamar Blue proliferation and Transwell migration assays, respectively. GFs including IGFBP 1, 2, 3, and 6, insulin, growth hormone, PDGF-AA, TGF-α, TGF-ß1, VEGF, and the anti-inflammatory cytokine, IL-1RA were detected. Membrane enclosed particles within exosome size range and expressing exosome tetraspanins CD81 and CD9 were identified. CCM significantly increased cell proliferation and induced stem cell migration. Analysis of CCM revealed presence of GFs, CKs, and EVs, including exosomes. The presence of multiple factors including exosomes within one formulation, the ability to promote cell proliferation and induce stem cell migration may reduce inflammation and pain, and augment tissue repair.


Assuntos
Extratos Celulares/farmacologia , Células Progenitoras Endoteliais/química , Fibroblastos/efeitos dos fármacos , Movimento Celular , Proliferação de Células , Células Cultivadas , Citocinas/metabolismo , Células Progenitoras Endoteliais/metabolismo , Exossomos/metabolismo , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Humanos , Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Tetraspaninas/metabolismo
18.
Ann Clin Lab Sci ; 50(5): 638-644, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33067209

RESUMO

OBJECTIVE: Tspan8 (tetraspanin 8) plays critical roles in cell adhesion and motility. Recently, Tspan8 overexpression has been found in various tumors. However, its expression status and prognostic significance in clear cell renal cell carcinoma (ccRCC) remains unknown. The objective of the present study was to assess the expression of Tspan8 and its correlation with clinicopathological features in ccRCC. METHODS: Tspan8 expression was detected in 150 cases of ccRCC and matched paracancerous tissues by immunohistochemistry (IHC) and its relevance with prognosis was analyzed. RESULTS: Our data showed that the high-expression rate of Tspan8 in ccRCC tissues was 74.0%, which was significantly higher than those in paracancerous kidney tissues (43.3%, P=0.001). Meanwhile, Tspan8 expression was positively correlated with tumor size and WHO/ISUP grade in ccRCC. Significantly, Kaplan-Meier analysis and log-rank test revealed that Tspan8 higher expression was associated with poorer overall survival (OS) in ccRCC patients (P<0.05). Cox regression analysis further showed that Tspan8 was a significant independent negative prognostic factor for these patients. CONCLUSION: Tspan8 is overexpressed in ccRCC and indicates poor prognosis, suggesting potential roles of Tspan8 in prognostication and targeted therapy.


Assuntos
Carcinoma de Células Renais/genética , Tetraspaninas/genética , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , China , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Tetraspaninas/metabolismo
19.
Int J Mol Sci ; 21(20)2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066349

RESUMO

The participation of extracellular vesicles in many cellular processes, including reproduction, is unquestionable. Although currently, the tetraspanin proteins found in extracellular vesicles are mostly applied as markers, increasing evidence points to their role in extracellular vesicle biogenesis, cargo selection, cell targeting, and cell uptake under both physiological and pathological conditions. In this review, we bring other insight into the involvement of tetraspanin proteins in extracellular vesicle physiology in mammalian reproduction. We provide knowledge regarding the involvement of extracellular vesicle tetraspanins in these processes in somatic cells. Furthermore, we discuss the future direction towards an understanding of their functions in the tissues and fluids of the mammalian reproductive system in gamete maturation, fertilization, and embryo development; their involvement in mutual cell contact and communication in their complexity.


Assuntos
Vesículas Extracelulares/metabolismo , Reprodução , Tetraspaninas/metabolismo , Animais , Células Germinativas/citologia , Células Germinativas/metabolismo , Humanos , Tetraspaninas/genética
20.
Sci Rep ; 10(1): 17972, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087788

RESUMO

Tetraspanins are four-span transmembrane proteins of host cells that facilitate infections by many pathogens. Burkholderia pseudomallei is an intracellular bacterium and the causative agent of melioidosis, a severe disease in tropical regions. This study investigated the role of tetraspanins in B. pseudomallei infection. We used flow cytometry to determine tetraspanins CD9, CD63, and CD81 expression on A549 and J774A.1 cells. Their roles in B. pseudomallei infection were investigated in vitro using monoclonal antibodies (MAbs) and recombinant large extracellular loop (EC2) proteins to pretreat cells before infection. Knockout of CD9 and CD81 in cells was performed using CRISPR Cas9 to confirm the role of tetraspanins. Pretreatment of A549 cells with MAb against CD9 and CD9-EC2 significantly enhanced B. pseudomallei internalization, but MAb against CD81 and CD81-EC2 inhibited MNGC formation. Reduction of MNGC formation was consistently observed in J774.A1 cells pretreated with MAbs specific to CD9 and CD81 and with CD9-EC2 and CD81-EC2. Data from knockout experiments confirmed that CD9 enhanced bacterial internalization and that CD81 inhibited MNGC formation. Our data indicate that tetraspanins are host cellular factors that mediated internalization and membrane fusion during B. pseudomallei infection. Tetraspanins may be the potential therapeutic targets for melioidosis.


Assuntos
Burkholderia pseudomallei/patogenicidade , Fusão Celular , Melioidose/microbiologia , Fagócitos/fisiologia , Tetraspaninas/fisiologia , Células A549 , Anticorpos Monoclonais , Sistemas CRISPR-Cas , Células Cultivadas , Células Gigantes/microbiologia , Humanos , Melioidose/terapia , Tetraspanina 28 , Tetraspanina 29 , Tetraspaninas/metabolismo
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