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1.
Cells ; 11(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36078095

RESUMO

Ectodomain shedding is an irreversible process to regulate inter- and intracellular signaling. Members of the a disintegrin and metalloprotease (ADAM) family are major mediators of ectodomain shedding. ADAM17 is involved in the processing of multiple substrates including tumor necrosis factor (TNF) α and EGF receptor ligands. Substrates of ADAM17 are selectively processed depending on stimulus and cellular context. However, it still remains largely elusive how substrate selectivity of ADAM17 is regulated. Tetraspanins (Tspan) are multi-membrane-passing proteins that are involved in the organization of plasma membrane micro-domains and diverse biological processes. Closely related members of the Tspan8 subfamily, including CD9, CD81 and Tspan8, are associated with cancer and metastasis. Here, we show that Tspan8 subfamily members use different strategies to regulate ADAM17 substrate selectivity. We demonstrate that in particular Tspan8 associates with both ADAM17 and TNF α and promotes ADAM17-mediated TNF α release through recruitment of ADAM17 into Tspan-enriched micro-domains. Yet, processing of other ADAM17 substrates is not altered by Tspan8. We, therefore, propose that Tspan8 contributes to tumorigenesis through enhanced ADAM17-mediated TNF α release and a resulting increase in tissue inflammation.


Assuntos
Proteínas ADAM , Desintegrinas , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteínas de Membrana , Especificidade por Substrato , Tetraspaninas/genética , Fator de Necrose Tumoral alfa/metabolismo
2.
J Extracell Vesicles ; 11(9): e12265, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36107309

RESUMO

CD47 regulates the trafficking of specific coding and noncoding RNAs into extracellular vesicles (EVs), and the RNA contents of CD47+ EVs differ from that of CD63+ EVs released by the same cells. Single particle interferometric reflectance imaging sensing combined with immunofluorescent imaging was used to analyse the colocalization of tetraspanins, integrins, and CD47 on EVs produced by wild type and CD47-deficient Jurkat T lymphoblast and PC3 prostate carcinoma cell lines. On Jurkat cell-derived EVs, ß1 and α4 integrin subunits colocalized predominantly with CD47 and CD81 but not with CD63 and CD9, conserving the known lateral interactions between these proteins in the plasma membrane. Although PC3 cell-derived EVs lacked detectable α4 integrin, specific association of CD81 with ß1 and CD47 was preserved. Loss of CD47 expression in Jurkat cells significantly reduced ß1 and α4 levels on EVs produced by these cells while elevating CD9+ , CD63+ , and CD81+ EVs. In contrast, loss of CD47 in PC3 cells decreased the abundance of CD63+ and CD81+ EVs. These data establish that CD47+ EVs are mostly distinct from EVs bearing the tetraspanins CD63 and CD9, but CD47 also indirectly regulates the abundance of EVs bearing these non-interacting tetraspanins via mechanisms that remain to be determined.


Assuntos
Carcinoma , Vesículas Extracelulares , Neoplasias da Próstata , Antígeno CD47/metabolismo , Carcinoma/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Integrina alfa4/metabolismo , Integrinas/metabolismo , Masculino , Próstata , Neoplasias da Próstata/metabolismo , RNA/metabolismo , Tetraspaninas/metabolismo
3.
Nat Commun ; 13(1): 5371, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36100608

RESUMO

The importance of fatty acid (FA) metabolism in cancer is well-established, yet the mechanisms underlying metabolic reprogramming remain elusive. Here, we identify tetraspanin CD37, a prognostic marker for aggressive B-cell lymphoma, as essential membrane-localized inhibitor of FA metabolism. Deletion of CD37 on lymphoma cells results in increased FA oxidation shown by functional assays and metabolomics. Furthermore, CD37-negative lymphomas selectively deplete palmitate from serum in mouse studies. Mechanistically, CD37 inhibits the FA transporter FATP1 through molecular interaction. Consequently, deletion of CD37 induces uptake and processing of exogenous palmitate into energy and essential building blocks for proliferation, and inhibition of FATP1 reverses this phenotype. Large lipid deposits and intracellular lipid droplets are observed in CD37-negative lymphoma tissues of patients. Moreover, inhibition of carnitine palmitoyl transferase 1 A significantly compromises viability and proliferation of CD37-deficient lymphomas. Collectively, our results identify CD37 as a direct gatekeeper of the FA metabolic switch in aggressive B-cell lymphoma.


Assuntos
Antígenos de Neoplasias , Linfoma de Células B , Animais , Antígenos de Neoplasias/metabolismo , Ácidos Graxos/metabolismo , Linfoma de Células B/genética , Camundongos , Palmitatos , Tetraspaninas/genética , Tetraspaninas/metabolismo
4.
Biochem Biophys Res Commun ; 628: 104-109, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36084547

RESUMO

Metastasis is a major cause of breast cancer mortality and the current study found histone demethylase, KDM2A, expression to be negatively correlated with breast cancer metastasis. KDM2A knockdown greatly promoted migration and invasion of breast cancer cells. The histone demethylase activity of KDM2A downregulated EGF transcription and suppressed the EGF-TSPAN8 pathway. Inhibition of breast cancer cell migration was also dependent on the histone demethylase activity of KDM2A. A novel mechanism of KDM2A-suppression of the EGF-TSPAN8 pathway which inhibited breast cancer cell migration and invasion is reported.


Assuntos
Neoplasias da Mama , Proteínas F-Box , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/fisiologia , Fator de Crescimento Epidérmico/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Tetraspaninas/metabolismo
5.
Int J Mol Sci ; 23(15)2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35955677

RESUMO

Small extracellular vesicles (sEV) hold enormous potential as biomarkers, drug carriers, and therapeutic agents. However, due to previous limitations in the phenotypic characterization of sEV at the single vesicle level, knowledge of cell type-specific sEV signatures remains sparse. With the introduction of next-generation sEV analysis devices, such as the single-particle interferometric reflectance imaging sensor (SP-IRIS)-based ExoView R100 platform, single sEV analyses are now possible. While the tetraspanins CD9, CD63, and CD81 were generally considered pan-sEV markers, it became clear that sEV of different cell types contain several combinations and amounts of these proteins on their surfaces. To gain better insight into the complexity and heterogeneity of sEV, we used the ExoView R100 platform to analyze the CD9/CD63/CD81 phenotype of sEV released by different cell types at a single sEV level. We demonstrated that these surface markers are sufficient to distinguish cell-type-specific sEV phenotypes. Furthermore, we recognized that tetraspanin composition in some sEV populations does not follow a random pattern. Notably, the tetraspanin distribution of sEV derived from mesenchymal stem cells (MSCs) alters depending on cell culture conditions. Overall, our data provide an overview of the cell-specific characteristics of sEV populations, which will increase the understanding of sEV physiology and improve the development of new sEV-based therapeutic approaches.


Assuntos
Vesículas Extracelulares , Células-Tronco Mesenquimais , Biomarcadores/metabolismo , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Tetraspanina 30/metabolismo , Tetraspaninas/metabolismo
6.
Biochem Biophys Res Commun ; 627: 146-151, 2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36037746

RESUMO

Extracellular vesicles (EVs) are particles released from most cell types delimited by a lipid bilayer. Small EVs (sEVs) are nanosized (<200 nm) and include exosomes. Brain-derived sEVs may provide a source for new biomarkers of brain status. CD9, CD63, and CD81 are major members of the tetraspanin family frequently used as sEV markers. However, according to a recent report, tetraspanins were not equally expressed in all sEVs, but rather show heterogeneity that reflects the expression levels in their secretory cells. We therefore investigated tetraspanin heterogeneity of sEVs in biofluids commonly used for clinical laboratory tests, and those in the brain. Expression levels and distributions of CD9, CD63 and CD81 on sEVs were determined in serum, plasma, and cerebrospinal fluid (CSF) samples collected from each healthy donor, and in post-mortem brain tissue samples. We found heterogeneous mixes of sEVs with various tetraspanin combinations among sEVs, and the predominant types and heterogeneous patterns of tetraspanins were specific to sample type. Hierarchical clustering revealed that brain sEVs were similar to those in the CSF, but different from those in peripheral blood. Our findings both provide basic information and contribute to the development of biomarkers for neurological and psychiatric disorders.


Assuntos
Exossomos , Vesículas Extracelulares , Biomarcadores/metabolismo , Encéfalo/metabolismo , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Tetraspanina 28/metabolismo , Tetraspanina 30/metabolismo , Tetraspaninas/metabolismo
7.
Mol Cell Probes ; 65: 101849, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35987447

RESUMO

BACKGROUND: As reported, long non-coding RNAs are a pivotal player in lung squamous cell carcinoma (LSCC) progression. We noticed the remarkably upregulated transmembrane-4-l-six-family-19 antisense RNA 1 (TM4SF19-AS1) in LSCC and further demonstrated the function it played in LSCC and the possible molecular mechanism. METHODS: Via bioinformatics approach, we evaluated TM4SF19-AS1 and TM4SF19 levels in LSCC tissue, and real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot revealed their mRNA and protein levels in LSCC cells. Cell Counting Kit-8 and colony formation assays analyzed the proliferation ability of LSCC cells, and cell adhesion ability was detected via cell adhesion assay. RNA immunoprecipitation and chromatin immunoprecipitation analyzed the underlying mechanism of TM4SF19-AS1 regulating its target, while methylation-specific PCR indicated the methylation level of TM4SF19-AS1. RESULTS: TM4SF19-AS1 was markedly upregulated in LSCC. Functional assays revealed that TM4SF19-AS1 could facilitate the proliferation and adhesion of LSCC. Besides, we revealed the mechanism of TM4SF19-AS1 regulation that it directly bound to WD repeat-containing protein 5 (WDR5), and was then recruited to TM4SF19 promoter region, which activated DNA demethylation, thereby suppressing malignant LSCC progression. CONCLUSION: Our research demonstrated that TM4SF19-AS1 affected LSCC cell proliferation by recruiting WDR5 to manipulate transmembrane-4-lsix-family-member-19 (TM4SF19), which offers a new observation on LSCC pathogenesis, indicating that TM4SF19-AS1 is able to be a promising target for LSCC treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , MicroRNAs , RNA Longo não Codificante , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Pulmão/metabolismo , Neoplasias Pulmonares/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Tetraspaninas
8.
PLoS One ; 17(7): e0271326, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35830446

RESUMO

OBJECTIVE: To systematically review the relationship between genotypes and clinical phenotypes of Familial exudative vitreoretinopathy (FEVR) to support risk estimation and therapeutic decisions. DESIGN: Systematic review with meta-analysis. DATA SOURCES: The data of our study were collected from PubMed, Embase, Web of Science, Cochrane, CBM, China National Knowledge Infrastructure (CNKI), WAN FANG and VIP databases since inception to August 2021. RESULTS: A total of 3257 patients from 32 studies were included according to the inclusion and exclusion criteria. Among all the cases, the mutation frequencies of LRP5, FZD4, NDP, TSPAN12, ZNF408 and KIF11 were 13.6%, 11.5%, 4.6%, 6.7%, 1.6%, and 5.7%, respectively. We found that the patients with NDP and FZD4 suffer more severe symptoms, among which 86.4% patients of NDP and 78.6% patients of FZD4 were in the advanced stage of FEVR. Retinal detachment is the most frequent symptom with patients of LRP5 and NDP mutations, accounting for 51.9% and 64.5%, respectively. For the patients with the mutation of TSPAN12, retinal fold is the most common clinical manifestation, and suffer the mildest clinical phenotypes compared with the other three genes. CONCLUSION: The results of the meta-analysis indicate that different types of genetic mutations occur at different frequencies. In addition, the clinical manifestations of FEVR are related to the type of gene mutation. Therefore, targeted treatment strategies and follow-up recommendations should be adopted for different pathogenic genes of FEVR.


Assuntos
Oftalmopatias Hereditárias , Doenças Retinianas , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Oftalmopatias Hereditárias/genética , Vitreorretinopatias Exsudativas Familiares , Receptores Frizzled/genética , Estudos de Associação Genética , Humanos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Mutação , Linhagem , Doenças Retinianas/genética , Tetraspaninas/genética , Fatores de Transcrição/genética
9.
Curr Oncol ; 29(7): 4689-4702, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35877232

RESUMO

The most frequently diagnosed histological types of cervical cancer (CC) are squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Clinically, the prognosis of both types is controversial. A molecular profile that distinguishes each histological subtype and predicts the prognosis would be of great benefit to CC patients. METHODS: The transcriptome of CC patients from The Cancer Genome Atlas (TCGA) was analyzed using the DESeq2 package to obtain the differentially expressed genes (DEGs) between ADC and SCC. The DEGs were validated on a publicly available Mexican-Mestizo patient transcriptome dataset (GSE56303). The global biological pathways involving the DEGs were obtained using the Webgestalt platform. The associations of the DEGs with Overall Survival (OS) were assessed. Finally, three DEGs were validated by RT-qPCR in an independent cohort of Mexican patients. RESULTS: The molecular profiles of ADC and SCC of the CC patients of the TCGA database and the Mexican-Mestizo cohort (GSE56303) were determined obtaining 1768 and 88 DEGs, respectively. Strikingly, 70 genes were concordant-with similar Log2FoldChange values-in both cohorts. The 70 DEGs were involved in IL-17, JAK/STAT, and Ras signaling. Kaplan-Meier OS analysis from the Mexican-Mestizo cohort showed that higher GABRB2 and TSPAN8 and lower TMEM40 expression were associated with better OS. Similar results were found in an independent Mexican cohort. CONCLUSIONS: Molecular differences were detected between the ADC and SCC subtypes; however, further studies are required to define the appropriate prognostic biomarker for each histological type.


Assuntos
Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , Adenocarcinoma/patologia , Biomarcadores , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Prognóstico , Tetraspaninas , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
10.
Dev Cell ; 57(13): 1630-1642.e4, 2022 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-35777354

RESUMO

Maintaining the integrity of the plasma membrane after cellular damage is essential for cell survival. However, it is unclear how cells repair large membrane injuries in vivo. Here, we report that the tetraspanin protein, TSP-15, is recruited to large membrane wounds and forms a ring-like structure in C. elegans epidermis and promotes membrane repair after an injury. TSP-15 recruits from the adjacent region underneath the plasma membrane to the wound site in a RAB-5-dependent manner upon membrane damage. Genetic and live-imaging analysis suggested that the endosomal sorting complex required for transport III (ESCRT III) is necessary for recruiting TSP-15 from the early endosome to the damaged membrane. Moreover, TSP-15 interacts with and is required for the accumulation of t-SNARE protein Syntaxin-2, which facilitates membrane repair. These findings provide valuable insights into the role of the conserved tetraspanin TSP-15 in the cellular repair of large wounds resulting from environmental insults.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Membrana Celular/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Epiderme/metabolismo , Proteínas SNARE/metabolismo , Tetraspaninas/genética , Tetraspaninas/metabolismo
11.
Endocr Regul ; 56(3): 216-226, 2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35843713

RESUMO

Objective. Nanographene oxide, an oxidation derivative of graphene, is considered to be one of the nanomaterials attractive for biomedical applications, although this nanomaterial is toxic. The increasing exploitation of graphene-based materials necessitates a comprehensive evaluation of the potential impact of these materials on the human health. Moreover, it is necessary to investigate in detail the mechanisms of its toxic effect on living cells particularly at the genome level. The present study aimed to evaluate the impact of low doses of nanographene oxide on the expression of key regulatory genes in normal human astrocytes. Methods. Normal human astrocytes, line NHA/TS, were exposed to low doses of nanographene oxide (1 and 4 ng/ml) for 24 h. RNA was extracted from the cells and used for cDNA synthesis. The expression levels of NAMPT, TSPAN13, BCAR3, BRCA1, PTGS2, P4HA1, and P4HA2 mRNAs as well as microRNAs were measured by quantitative polymerase chain reaction. Results. It was found that the low doses of nanographene oxide induced a dysregulation in the expression of the key regulatory genes in normal human astrocytes in dose-dependent (1 and 4 ng/ml) and gene-specific manner. Nanographene oxide also strongly suppressed the expression of NAMPT, BCAR3, and TSPAN13 genes and significantly up-regulated BRCA1, PTGS2, P4HA1, and P4HA2 ones with a more significant effect in P4HA1 and P4HA2 genes. The expression of miR-96-5p and miR-145-5p was also down-regulated in astrocytes treated with nanographene oxide in a dose-dependent manner. Conclusion. The data obtained demonstrate that the low doses of nanographene oxide disturbed the genome functions by changing the expression levels of key regulatory genes in gene-specific and dose-dependent manner. Moreover, a higher dose of nanographene oxide induced more pronounced changes in expression of genes indicating for both genotoxic and neurotoxic possible effects in the normal human astrocytes.


Assuntos
Grafite , MicroRNAs , Astrócitos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Expressão Gênica , Grafite/metabolismo , Grafite/toxicidade , Humanos , MicroRNAs/genética , Óxidos/metabolismo , Óxidos/toxicidade , Tetraspaninas/genética , Tetraspaninas/metabolismo
12.
J Extracell Vesicles ; 11(7): e12248, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35879268

RESUMO

Extracellular vesicles (EVs) have shown promise as potential therapeutics for the treatment of various diseases. However, their rapid clearance after administration could be a limitation in certain therapeutic settings. To solve this, an engineering strategy is employed to decorate albumin onto the surface of the EVs through surface display of albumin binding domains (ABDs). ABDs were either included in the extracellular loops of select EV-enriched tetraspanins (CD63, CD9 and CD81) or directly fused to the extracellular terminal of single transmembrane EV-sorting domains, such as Lamp2B. These engineered EVs exert robust binding capacity to human serum albumins (HSA) in vitro and mouse serum albumins (MSA) after injection in mice. By binding to MSA, circulating time of EVs dramatically increases after different routes of injection in different strains of mice. Moreover, these engineered EVs show considerable lymph node (LN) and solid tumour accumulation, which can be utilized when using EVs for immunomodulation, cancer- and/or immunotherapy. The increased circulation time of EVs may also be important when combined with tissue-specific targeting ligands and could provide significant benefit for their therapeutic use in a variety of disease indications.


Assuntos
Vesículas Extracelulares , Neoplasias , Albuminas/análise , Animais , Tempo de Circulação Sanguínea , Modelos Animais de Doenças , Vesículas Extracelulares/química , Humanos , Linfonodos , Camundongos , Neoplasias/metabolismo , Tetraspaninas/análise
13.
Mol Genet Genomic Med ; 10(9): e2021, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35876299

RESUMO

PURPOSE: To expand the mutation spectrum of patients with familial exudative vitreoretinopathy (FEVR) disease. PARTICIPANTS: 74 probands (53 families and 21 sporadic probands) with familial exudative vitreoretinopathy (FEVR) disease and their available family members (n = 188) were recruited for sequencing. METHODS: Panel-based targeted screening was performed on all subjects. Before sanger sequencing, variants of LRP5, NDP, FZD4, TSPAN12, ZNF408, KIF11, RCBTB1, JAG1, and CTNNA1 genes were verified by a series of bioinformatics tools and genotype-phenotype co-segregation analysis. RESULTS: 40.54% (30/74) of the probands were sighted to possess at least one etiological mutation of the nine FEVR-causative genes. The etiological mutation detection rate was 37.74% (20/53) in family-attainable probands while 47.62% (10/21) in sporadic cases. The diagnosis rate of patients in the early-onset subgroup (≤5 years old, 45.4%) is higher than that of the children or adolescence-onset subgroup (6-16 years old, 42.1%) and the late-onset subgroup (≥17 years old, 39.4%). A total of 36 etiological mutations were identified in this study, comprising 26 novel mutations and 10 reported mutations. LRP5 was the most prevalent mutant gene among the 36 mutation types with a percentage of 41.67% (15/36). Followed by FZD4 (10/36, 27.78%), TSPAN12 (5/36, 13.89%), NDP (4/36, 11.11%), KIF11 (1/36, 2.78%), and RCBTB1 (1/36, 2.78%). Among these mutations, 63.89% (23/36) were missense mutations, 25.00% (9/36) were frameshift mutations, 5.56% (2/36) were splicing mutations, 5.56% (2/36) were nonsense mutations. Moreover, the clinical pathogenicity of these variants was defined according to American College of Medical Genetics (ACMG) and genomics guidelines: 41.67% (15/36) were likely pathogenic variants, 27.78% (10/36) pathogenic variants, 30.55% (11/36) variants of uncertain significance. No etiological mutations discovered in the ZNF408, JAG1, and CTNNA1 genes in this FEVR cohort. CONCLUSIONS: We systematically screened nine FEVR disease-associated genes in a cohort of 74 Chinese probands with FEVR disease. With a detection rate of 40.54%, 36 etiological mutations of six genes were authenticated in 30 probands, including 26 novel mutations and 10 reported mutations. The most prevalent mutated gene is LRP5, followed by FZD4, TSPAN12, NDP, KIF11, and RCBTB1. In total, a de novo mutation was confirmed. Our study significantly clarified the mutation spectrum of variants bounded up to FEVR disease.


Assuntos
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Doenças Retinianas , Códon sem Sentido , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Vitreorretinopatias Exsudativas Familiares/genética , Receptores Frizzled/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Mutação , Linhagem , Doenças Retinianas/genética , Tetraspaninas/genética , Fatores de Transcrição
14.
Cell Biol Int ; 46(10): 1693-1703, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35904232

RESUMO

TSPAN8 mediates signal transduction from extracellular cues and regulates cell development, activation, growth, and motility. However, whether TSPAN8 is involved in the progression of diabetic nephropathy (DN) remains unclear. This study aimed to explore the potential functional roles of TSPAN8 in regulating autophagy and apoptosis of HK-2 cells induced by high glucose (HG). RT-PCR and western blot analysis (WB) were employed to detect TSPAN8 levels in the blood samples of DN patients as well as in HG-induced HK-2 cells. Cell proliferation of HK-2 cells was examined by CCK-8 assay, and apoptosis was analyzed by flow cytometry. The functional role of TSPAN8 was evaluated by the transfection of TSPAN8 expression plasmid. Results showed that TSPAN8 level was significantly reduced in the blood samples of DN patients and HG-induced HK-2 cell lines. TSPAN8 overexpression rescued HG-induced apoptosis in HK-2 cells. TSPAN8 could form a complex with Rictor and mTORC2. TSPAN8 overexpression suppressed HG-induced autophagy in HK-2 cells, which was dependent on mTOR activity. In conclusion, the present study showed that TSPAN8 mitigates HG-induced autophagy and apoptosis in HK-2 cells, which may serve as candidate target for DN treatment.


Assuntos
Nefropatias Diabéticas , Alvo Mecanístico do Complexo 2 de Rapamicina , MicroRNAs , Tetraspaninas , Apoptose , Autofagia , Nefropatias Diabéticas/metabolismo , Glucose/metabolismo , Glucose/farmacologia , Humanos , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , MicroRNAs/metabolismo , Tetraspaninas/metabolismo
15.
Sci Rep ; 12(1): 11027, 2022 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-35773268

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is categorized as the leading cause of cancer mortality worldwide. However, its predictive markers for long-term survival are not well known. It is interesting to delineate individual-specific perturbed genes when comparing long-term (LT) and short-term (ST) PDAC survivors and integrate individual- and group-based transcriptome profiling. Using a discovery cohort of 19 PDAC patients from CHU-Liège (Belgium), we first performed differential gene expression analysis comparing LT to ST survivor. Second, we adopted systems biology approaches to obtain clinically relevant gene modules. Third, we created individual-specific perturbation profiles. Furthermore, we used Degree-Aware disease gene prioritizing (DADA) method to develop PDAC disease modules; Network-based Integration of Multi-omics Data (NetICS) to integrate group-based and individual-specific perturbed genes in relation to PDAC LT survival. We identified 173 differentially expressed genes (DEGs) in ST and LT survivors and five modules (including 38 DEGs) showing associations to clinical traits. Validation of DEGs in the molecular lab suggested a role of REG4 and TSPAN8 in PDAC survival. Via NetICS and DADA, we identified various known oncogenes such as CUL1 and TGFB1. Our proposed analytic workflow shows the advantages of combining clinical and omics data as well as individual- and group-level transcriptome profiling.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/patologia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pancreáticas/patologia , Tetraspaninas/metabolismo , Transcriptoma
16.
Physiol Behav ; 254: 113894, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35764142

RESUMO

CD81, a member of the tetraspanin family, plays important roles in many physiological processes, such as cell motility, attachment, and entry. Yet, CD81 functions in the brain remain unclear. In this study, we investigated the effects of CD81 knockdown, using lentiviral vectors (LV), on anxiety- and ethanol-related behaviors. For this purpose, mice were stereotaxically injected with CD81 shRNA-expressing LV into the nucleus accumbens (Nacc) and were assessed for anxiety-like behavior using the elevated plus maze (EPM) and open field (OF) tests. Alcohol's sedative effects were studied using loss-of-righting-reflex (LORR) and voluntary ethanol intake was assessed using a two-bottle choice (TBC) procedure. Results showed that mice depleted of CD81 exhibited an anxiolytic-like response in the EPM and OF tests with no effect on locomotor activity. In addition, genetic reduction of CD81 in the Nacc increased mice' sensitivity to alcohol's sedative effects in the LORR test, although plasma alcohol concentrations were unaffected. Interestingly, CD81 loss-of-function-induced anxiolysis was accompanied by a significant decrease in ethanol, but not saccharin nor quinine, intake in the TBC procedure. Finally, and following CD81 mRNA quantification, Pearson's correlations showed a significant positive relationship between accumbal CD81 mRNA with anxiety and ethanol-related behaviors. Our data indicate that CD81 is implicated in the pathogenesis of anxiety and alcoholism. Indeed the targeted disruption of CD81, with the resultant decrease in CD81 mRNA in the Nacc, converted ethanol-"preferring" mice into ethanol "non-preferring" mice. Collectively, these findings demonstrate that future CD81-targeted pharmacotherapies may be beneficial for the treatment of anxiety and alcoholism.


Assuntos
Alcoolismo , Etanol , Consumo de Bebidas Alcoólicas/genética , Animais , Ansiedade , Hipnóticos e Sedativos , Camundongos , Núcleo Accumbens , RNA Mensageiro , Tetraspanina 28 , Tetraspaninas
17.
Nat Cell Biol ; 24(6): 825-832, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35654840

RESUMO

Various mechanisms contribute to membrane repair1-8 but the machinery that mediates the repair of large wounds on the plasma membrane is less clear. We found that shortly after membrane damage, Tetraspanin-enriched macrodomains are assembled around the damage site. Tetraspanin-enriched macrodomains are in the liquid-ordered phase and form a rigid ring around the damaged site. This restricts the spread of the damage and prevents membrane disintegration, thus facilitating membrane repair by other mechanisms. Functionally, Tetraspanin 4 helps cells mitigate damage caused by laser, detergent, pyroptosis and natural killer cells. We propose that assembly of Tetraspanin-enriched macrodomains creates a physical barrier to contain membrane damage.


Assuntos
Tetraspaninas , Membrana Celular/metabolismo , Tetraspaninas/metabolismo
18.
Genes (Basel) ; 13(6)2022 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-35741813

RESUMO

Ischemic cardiomyopathy (ICM) caused by coronary artery disease always leads to myocardial infarction and heart failure. Identification of novel transcriptional regulators in ICM is an effective method to establish new diagnostic and therapeutic strategies. In this study, we used two RNA-seq datasets and one microarray dataset from different studies, including 25 ICM and 21 non-failing control (NF) samples of human left ventricle tissues for further analysis. In total, 208 differentially expressed genes (DEGs) were found by combining two RNA-seq datasets with batch effects removed. GO and KEGG analyses of DEGs indicated that the response to wounding, positive regulation of smooth muscle contraction, chromatin, PI3K-Akt signaling pathway, and transporters pathways are involved in ICM. Simple Enrichment Analysis found that NFIC-binding motifs are enriched in promoter regions of downregulated genes. The Gene Importance Calculator further proved that NFIC is vital. NFIC and its downstream genes were verified in the validating microarray dataset. Meanwhile, in rat cardiomyocyte cell line H9C2 cells, two genes (Tspan1 and Hopx) were confirmed, which decreased significantly along with knocking down Nfic expression. In conclusion, NFIC participates in the ICM process by regulating TSPAN1 and HOPX. NFIC and its downstream genes may be marker genes and potential diagnostic and therapeutic targets for ICM.


Assuntos
Cardiomiopatias , Proteínas de Homeodomínio , Isquemia Miocárdica , Fatores de Transcrição NFI , Tetraspaninas , Proteínas Supressoras de Tumor , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Biologia Computacional , Proteínas de Homeodomínio/genética , Humanos , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Fatores de Transcrição NFI/genética , RNA-Seq , Tetraspaninas/genética , Proteínas Supressoras de Tumor/genética
19.
Eur J Cell Biol ; 101(3): 151229, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35500468

RESUMO

Tetraspanin proteins organize membrane nanodomains related to cell adhesion and migration. An essential feature conserved along the superfamily is their cone-shaped tertiary structure, which allows tetraspanins to be enriched in highly curved membrane structures. Their conical shape, together with their ability to associate to transmembrane receptors and to bind to cystoskeletal and signaling scaffolds, are key in their ability to regulate endosomal network dynamics and Extracellular Vesicle biogenesis and cargo selection. Recent evidence suggests that tetraspanins have a relevant impact in mitochondria turnover and regulation of cellular metabolism. In this review we highlight those reports that point to tetraspanins as key regulators in the communication between the endosomal network, EVs and the cellular metabolism.


Assuntos
Endossomos , Tetraspaninas , Adesão Celular , Endossomos/metabolismo , Transdução de Sinais , Tetraspaninas/metabolismo
20.
J Immunol Res ; 2022: 9051229, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35600044

RESUMO

Tetraspanins (TSPANs) play crucial roles in cell adhesion, migration, and metastasis of human cancer. However, there is no study in revealing the aspects of TSPAN9 traits and its functions in hepatocellular carcinoma (HCC) prognosis. Our study is the first to portray the TSPAN9 expression in HCC tissues with immunohistochemistry (IHC) analysis. Subsequently, a series of bioinformatics analyses such as expression estimation, survival assessment, and correlation analysis were implemented to dig out the possible upstream noncoding RNAs (ncRNAs) for TSPAN9 in HCC. In this way, the relevance within TSPAN9 and tumor immunity was then explored. We found that the TSPAN9 was downregulated in HCC tissues and had a correlation with HCC prognosis. Furthermore, we identified that the AL139383.1-hsa-miR-9-5p axis was the upstream ncRNA-related pathway most associated with TSPAN9 in HCC. Besides that, expression of TSPAN9 held a significantly negative correlation with tumor immunocyte infiltration as well as immune checkpoint CTLA4. TSPAN9-related immunomodulators were mainly enriched in T cell activation, leukocyte cell-cell adhesion, regulation of T cell activation, and regulation of leukocyte cell-cell adhesion signaling pathway. In conclusion, our results indicated that hsa-miR-9-5p-mediated downregulation of TSPAN9 was associated with poor HCC prognosis, immune-related signaling pathway, and tumor immune infiltration.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Prognóstico , Tetraspaninas/genética , Tetraspaninas/metabolismo
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