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1.
Zhonghua Xue Ye Xue Za Zhi ; 42(6): 495-501, 2021 Jun 14.
Artigo em Chinês | MEDLINE | ID: mdl-34384156

RESUMO

Objective: This study aims to explore the clinical characteristics of T-cell large granular lymphocyte leukemia (T-LGLL) patients with STAT3 mutation status and provide a reference for clinical management of such patients. Methods: The clinical data of T-LGLL patients between 2009 and 2019 in Jiangsu Province Hospital were retrospectively analyzed. Differences in baseline clinical data, treatment responses, and survival outcomes in patients with STAT3 mutations or with no mutations were compared. Results: A total of 80 patients were included, including 66 patients without STAT3 mutation and 14 patients (17.5%) with STAT3 mutation. The frequency of Y640F mutation was the highest (42.9%) . Compared with non STAT3 mutation group, STAT3 mutation group had lower HGB (67.5 g/L vs 82.5 g/L, P=0.018) , lower neutrophil count (0.665×10(9)/L vs 1.465×10(9)/L, P<0.001) , higher LDH (229 U/L vs 198 U/L, P=0.041) , higher ferritin (402.5 g/L vs 236.0 g/L, P=0.029) , higher expression rate of TCR Vß subfamily (89.2% vs 65.4%, P=0.014) and higher proportion of patients with treatment indications (100% vs 74%, P=0.033) . The complete remission rates of STAT3 mutation group and non mutation group were 38.5% and 32.7%, respectively, with no significant difference (P=0.748) . The overall response rate of first-line immunosuppressive therapy in STAT3 mutation group and non mutation group were 69.2% and 69.4%, respectively, with no significant difference (P=1.000) . The median follow-up time was 63 (2-121) months. There was no significant difference in the overall survival time between the two groups (P=0.170) . Conclusions: T-LGLL patients with STAT3 mutations seems to be correlated with an increased tumor burden and high treatment demand, and had a good response to first-line immunotherapies. The prognostic significance of STAT3 mutation in T-LGLL patients requires further validation.


Assuntos
Leucemia Linfocítica Granular Grande , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia Linfocítica Granular Grande/genética , Mutação , Estudos Retrospectivos , Fator de Transcrição STAT3/genética , Linfócitos T
2.
Am J Hum Genet ; 108(9): 1590-1610, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34390653

RESUMO

Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.


Assuntos
Carcinoma de Células Renais/genética , Cromossomos Humanos Par 14 , Proteínas de Ligação a DNA/genética , Loci Gênicos , Neoplasias Renais/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Linhagem Celular Tumoral , Cromatina/química , Cromatina/imunologia , Montagem e Desmontagem da Cromatina/imunologia , Citocinas/genética , Citocinas/imunologia , Proteínas de Ligação a DNA/imunologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT3/imunologia , Linfócitos T Citotóxicos , Fatores de Transcrição/imunologia
3.
Oxid Med Cell Longev ; 2021: 7385160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457118

RESUMO

Obesity is considered as a risk factor of osteoarthritis (OA), but the precise relationship is still poorly understood. Leptin, one of the most relevant factors secreted by adipose tissues, plays an important role in the pathogenesis of OA. Our aim was to investigate the regulation and molecular mechanism of the leptin signaling pathway in obesity-related OA. SD rats were fed with a high-fat diet (HFD) for 5, 15, and 27 weeks. The levels of leptin in serum increased from W5, while in the synovial fluid increased from W15. The histological evaluation showed that the pathological changes of OA occurred at 27 weeks rather than 5 or 15 weeks. We also found that leptin induced CD14/TLR4 activation by the JAK2-STAT3 signaling pathway to promote OA. Moreover, silencing SOCS3 enhanced leptin-induced JAK2-STAT3-CD14/TLR4 activation in rat primary chondrocytes. Our findings indicated that leptin may be one of the initiating factors of obesity-related OA. TLR4 is at least partially regulated by leptin through the JAK2-STAT3-CD14 pathway. Meanwhile, SOCS3 acting as a negative feedback inhibitor of leptin signaling presented a potential therapeutic prospect for obesity-related OA. Our study provided new evidence suggesting the key role of leptin in mediating obesity-related OA process and its underlying mechanisms.


Assuntos
Regulação da Expressão Gênica , Janus Quinase 2/metabolismo , Leptina/metabolismo , Obesidade/complicações , Osteoartrite/patologia , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Janus Quinase 2/genética , Masculino , Osteoartrite/etiologia , Osteoartrite/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética , Receptor 4 Toll-Like/genética
4.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361081

RESUMO

Cancer cachexia is a common deleterious paraneoplastic syndrome that represents an area of unmet clinical need, partly due to its poorly understood aetiology and complex multifactorial nature. We have interrogated multiple genetically defined larval Drosophila models of tumourigenesis against key features of human cancer cachexia. Our results indicate that cachectic tissue wasting is dependent on the genetic characteristics of the tumour and demonstrate that host malnutrition or tumour burden are not sufficient to drive wasting. We show that JAK/STAT and TNF-α/Egr signalling are elevated in cachectic muscle and promote tissue wasting. Furthermore, we introduce a dual driver system that allows independent genetic manipulation of tumour and host skeletal muscle. Overall, we present a novel Drosophila larval paradigm to study tumour/host tissue crosstalk in vivo, which may contribute to future research in cancer cachexia and impact the design of therapeutic approaches for this pathology.


Assuntos
Caquexia/patologia , Carcinogênese/patologia , Modelos Animais de Doenças , Larva/crescimento & desenvolvimento , Neoplasias/complicações , Animais , Caquexia/etiologia , Caquexia/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Drosophila , Perfilação da Expressão Gênica , Humanos , Janus Quinases/genética , Janus Quinases/metabolismo , Larva/genética , Larva/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
5.
Ecotoxicol Environ Saf ; 223: 112570, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352581

RESUMO

BaP and DBP are ubiquitously and contemporaneously present in the environment. However, Current studies largely concentrate on the effects of a single pollutant (BaP or DBP). The liver is vital for biogenic activities. The effects of BaP and DBP co-exposure on liver remain unclear. Thus, we treated human normal liver cell (L02 cell) with BaP or/and DBP. We found that compared to individual exposure, co-exposure to BaP and DBP induced further increased levels of AST and ALT. BaP and DBP co-exposure caused further increased levels of IL-2, IL-6, and TNF-α, decreased IL-10 level, and a higher percentage of apoptotic cells and S-phase arrest cells. BaP and DBP co-exposure worsen the decrease of miR-122-5p level and chaos of SOCS1/STAT3 signaling. Dual-luciferase reporter gene assays showed that SOCS1 was a validated target of miR-122-5p. miR-122-5p overexpression alleviated the increased SOCS1 expression, decreased phospho-STAT3 expression, decreased IL-10 level, increased TNF-α levels, increased percentage of apoptosis and S-phase arrest, and cytotoxicity induced by BaP and DBP co-exposure in hepatocytes. These results suggested that miR-122-5p negatively regulated the synergistic effects on apoptosis and disorder of inflammatory factor secretion involved in hepatocyte injury caused by BaP and DBP co-exposure through targeting SOCS1/STAT3 signaling.


Assuntos
MicroRNAs , Apoptose , Hepatócitos/metabolismo , Humanos , MicroRNAs/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Fator de Necrose Tumoral alfa/genética
6.
Nat Commun ; 12(1): 4821, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376672

RESUMO

Subclonal genetic heterogeneity and their diverse gene expression impose serious problems in understanding the behavior of cancers and contemplating therapeutic strategies. Here we develop and utilize a capture-based sequencing panel, which covers host hotspot genes and the full-length genome of human T-cell leukemia virus type-1 (HTLV-1), to investigate the clonal architecture of adult T-cell leukemia-lymphoma (ATL). For chronologically collected specimens from patients with ATL or pre-onset individuals, we integrate deep DNA sequencing and single-cell RNA sequencing to detect the somatic mutations and virus directly and characterize the transcriptional readouts in respective subclones. Characteristic genomic and transcriptomic patterns are associated with subclonal expansion and switches during the clinical timeline. Multistep mutations in the T-cell receptor (TCR), STAT3, and NOTCH pathways establish clone-specific transcriptomic abnormalities and further accelerate their proliferative potential to develop highly malignant clones, leading to disease onset and progression. Early detection and characterization of newly expanded subclones through the integrative analytical platform will be valuable for the development of an in-depth understanding of this disease.


Assuntos
Genoma Viral/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Leucemia-Linfoma de Células T do Adulto/genética , Análise de Célula Única/métodos , Transcriptoma/genética , Adulto , Linhagem Celular Tumoral , Proliferação de Células/genética , Células Cultivadas , Evolução Clonal/genética , Células Clonais/metabolismo , Células Clonais/patologia , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Células Jurkat , Leucemia-Linfoma de Células T do Adulto/patologia , Leucemia-Linfoma de Células T do Adulto/virologia , Mutação , RNA-Seq/métodos , Receptor Notch1/genética , Receptores de Antígenos de Linfócitos T/genética , Fator de Transcrição STAT3/genética
7.
Front Cell Infect Microbiol ; 11: 669394, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307193

RESUMO

Signal transducer and activator of transcription-3 (STAT3) plays an important role in biological balance. Our and others previous studies implied that STAT3 had a great effect on fast-acting innate immunity against tuberculosis (TB). We hypothesized that stat3 SNP down-regulation of STAT3 leads to a change in susceptibility to TB in humans. To test this hypothesis, we investigated STAT3 SNPs using SNP scan™ technique in a case-control study of TB patients (n = 470) and HC subjects (n = 356), and then conducted functional studies of them using cellular models. We found that SNPs in STAT3 3`-UTR of rs1053004 TT and rs1053005 AA genotypes or T-A haplotype were associated with susceptibility to TB or TB severity. While the TT/AA genotype correlated with the low constitutive expression of stat3 and IL-17A in PBMC, the variant stat3 of rs1053004-rs1053005 T-A haplotype indeed reduced stat3 expression in reporter assays. Interestingly, host PBMC expressing the rs1053005 AA genotype and low constitutive stat3 exhibited the reduced ability to mount fast-acting innate immunity against mycobacterial infection in cellular models. Finally, mechanistic experiments showed that the STAT3 down-regulation broadly depressed STAT3 downstream anti-mycobacterial activities involving VDR-related CAMP pathway as well as IL-32, iNOS and autophagy mechanisms, leading to an enhanced mycobacterial infection. The findings of this study suggest that low constitutive stat3 derived from the TT/AA genotype/T-A haplotype acts to down-regulate STAT3, depressing multiple anti-mycobacterial pathways/mechanisms downstream, which leads to an enhanced mycobacterial infection or TB in high-risk individuals.


Assuntos
Leucócitos Mononucleares , Tuberculose , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT3/genética , Tuberculose/genética
8.
Aging (Albany NY) ; 13(13): 17536-17547, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233296

RESUMO

Pathological manifestations in either heart or kidney impact the function of the other and form the basis for the development of cardiorenal syndrome. However, the mechanism or factors involved in such scenario are not completely elucidated. In our study, to find the correlation between late fetal gene expression in diabetic hearts and their influence on diabetic nephropathy, we created a rat model with cardiac specific overexpression of IGF-IIRα, which is an alternative splicing variant of IGFIIR, expressed in pathological hearts. In this study, transgenic rats over expressing cardiac specific IGF-IIRα and non-transgenic animal models established in SD rats were administered with single dose of streptozotocin (STZ, 55 mg/Kg) to induce Type I diabetes. The correlation between IGF-IIRα and kidney damages were further determined based on their intensity of damage in the kidneys. The results show that cardiac specific overexpression of IGF-IIRα elevates the diabetes associated inflammation and morphological changes in the kidneys. The diabetic transgenic rats showed advancement in the pathological features such a renal tubular damage, collagen accumulation and enhancement in STAT3 associated mechanism of renal fibrosis. The results therefore show that that IGF-IIRα expression in the heart during pathological condition may worsen symptoms of diabetic nephropathy in rats.


Assuntos
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Receptor IGF Tipo 2/genética , Animais , Apoptose/genética , Colágeno/metabolismo , Fibrose , Regulação da Expressão Gênica , Rim/patologia , Túbulos Renais/patologia , Masculino , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Fator de Transcrição STAT3/genética
9.
Redox Biol ; 45: 102051, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34217063

RESUMO

Aberrant placental angiogenesis is associated with fetal intrauterine growth restriction (IUGR), but the mechanism underlying abnormal placental angiogenesis remains largely unknown. Here, lower vessel density and higher expression of NADPH oxidases 2 (Nox2) were observed in the placentae for low birth weight (LBW) fetuses versus normal birth weight (NBW) fetuses, with a negative correlation between Nox2 and placental vessel density. Moreover, it was revealed for the first time that Nox2 deficiency facilitates angiogenesis in vitro and in vivo, and vascular endothelial growth factor-A (VEGF-A) has an essential role in Nox2-controlled inhibition of angiogenesis in porcine vascular endothelial cells (PVECs). Mechanistically, Nox2 inhibited phospho-signal transducer and activator of transcription 3 (p-STAT3) in the nucleus by inducing the production of mitochondrial reactive oxygen species (ROS). Dual-luciferase assay confirmed that knockdown of Nox2 reduces the expression of VEGF-A in an STAT3 dependent manner. Our results indicate that Nox2 is a potential target for therapy by increasing VEGF-A expression to promote angiogenesis and serves as a prognostic indicator for fetus with IUGR.


Assuntos
NADPH Oxidase 2/metabolismo , Neovascularização Fisiológica , Placenta , Fator A de Crescimento do Endotélio Vascular , Animais , Células Endoteliais/metabolismo , Feminino , Placenta/metabolismo , Gravidez , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/genética , Suínos , Fator A de Crescimento do Endotélio Vascular/genética
10.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299065

RESUMO

One of the changes brought about by Wallerian degeneration distal to nerve injury is disintegration of axonal mitochondria and consequent leakage of mitochondrial DNA (mtDNA)-the natural ligand for the toll-like receptor 9 (TLR9). RT-PCR and immunohistochemical or Western blot analyses were used to detect TLR9 mRNA and protein respectively in the lumbar (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) ipsilateral and contralateral to a sterile unilateral sciatic nerve compression or transection. The unilateral sciatic nerve lesions led to bilateral increases in levels of both TLR9 mRNA and protein not only in the lumbar but also in the remote cervical DRG compared with naive or sham-operated controls. This upregulation of TLR9 was linked to activation of the Nuclear Factor kappa B (NFκB) and nuclear translocation of the Signal Transducer and Activator of Transcription 3 (STAT3), implying innate neuronal immune reaction and a pro-regenerative state in uninjured primary sensory neurons of the cervical DRG. The relationship of TLR9 to the induction of a pro-regenerative state in the cervical DRG neurons was confirmed by the shorter lengths of regenerated axons distal to ulnar nerve crush following a previous sciatic nerve lesion and intrathecal chloroquine injection compared with control rats. The results suggest that a systemic innate immune reaction not only triggers the regenerative state of axotomized DRG neurons but also induces a pro-regenerative state further along the neural axis after unilateral nerve injury.


Assuntos
Gânglios Espinais/citologia , Imunidade Inata/imunologia , Neurônios/citologia , Neurônios/imunologia , Fator de Transcrição STAT3/metabolismo , Neuropatia Ciática/terapia , Receptor Toll-Like 9/metabolismo , Animais , Masculino , Ratos , Ratos Wistar , Fator de Transcrição STAT3/genética , Neuropatia Ciática/imunologia , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Receptor Toll-Like 9/genética
11.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206382

RESUMO

Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery-Dreifuss muscular dystrophy (EDMD). Evidence is accumulating that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has not been fully elucidated. Here, we show that emerin downregulates Signal transducer and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus kinase (JAK). Deletion mutation experiments show that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacts directly and co-localizes with STAT3 in the nuclear membrane. Emerin knockdown induces STAT3 target genes Bcl2 and Survivin to increase cell survival signals and suppress hydrogen peroxide-induced cell death in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin, by assembling with BAF and lamin A/C, acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induces STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and may be a new therapeutic target for treatment.


Assuntos
Proteínas de Membrana/metabolismo , Membrana Nuclear/metabolismo , Proteínas Nucleares/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Células A549 , Núcleo Celular/metabolismo , Sobrevivência Celular , Regulação da Expressão Gênica , Humanos , Janus Quinases/metabolismo , Músculo Esquelético/metabolismo , Distrofias Musculares/etiologia , Distrofias Musculares/metabolismo , Distrofias Musculares/patologia , Mutação , Ligação Proteica , Fator de Transcrição STAT3/genética , Fatores de Transcrição/metabolismo
12.
Stem Cell Res Ther ; 12(1): 396, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34256837

RESUMO

BACKGROUND: Effective treatments for acute-on-chronic liver failure (ACLF) are lacking. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been applied in tissue regeneration and repair, acting through paracrine effects, cell fusion, and actual transdifferentiation. The present study was designed to investigate the therapeutic potential of hUC-MSCs in acute-on-chronic liver injury (ACLI) and ACLF rat models. METHODS: Wistar rats aged 6 weeks were intraperitoneally administered porcine serum (PS) at a dose of 0.5 mL twice per week for 11 weeks to generate an immune liver fibrosis model. After 11 weeks, rats with immune liver fibrosis were injected intravenously with lipopolysaccharide (LPS) to induce an ACLI model or combined LPS and D-galactosamine (D-GalN) to induce an ACLF model. The rats with ACLI or ACLF were injected intravenously with 2×106 hUC-MSCs, 4×106 hUC-MSCs, or 0.9% sodium chloride as a control. The rats were sacrificed at 1, 2, 4, and 6 weeks (ACLI rats) or 4, 12, and 24 h (ACLF rats). The blood and liver tissues were collected for biochemical and histological investigation. RESULTS: The application of hUC-MSCs in rats with ACLI and ACLF led to a significant decrease in the serum levels of ALT, AST, TBil, DBil, ALP, ammonia, and PT, with ALB gradually returned to normal levels. Inflammatory cell infiltration and collagen fiber deposition in liver tissues were significantly attenuated in ACLI rats that received hUC-MSCs. Inflammatory cell infiltration and apoptosis in liver tissues of ACLF rats that received hUC-MSCs were significantly attenuated. Compared with those in the rats that received 0.9% sodium chloride, a significant reduction in proinflammatory cytokine levels and elevated serum levels of hepatocyte growth factor (HGF) were found in ACLF rats that received hUC-MSCs. Furthermore, Notch, IFN-γ/Stat1, and IL-6/Stat3 signaling were inhibited in ACLI/ACLF rats that received hUC-MSCs. CONCLUSIONS: hUC-MSC transplantation can improve liver function, the degree of fibrosis, and liver damage and promote liver repair in rats with ACLI or ACLF, mediated most likely by inhibiting Notch signaling and reversing the imbalance of the Stat1/Stat3 pathway.


Assuntos
Insuficiência Hepática Crônica Agudizada , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Insuficiência Hepática Crônica Agudizada/terapia , Animais , Humanos , Ratos , Ratos Wistar , Fator de Transcrição STAT1 , Fator de Transcrição STAT3/genética , Suínos , Cordão Umbilical
13.
J Int Med Res ; 49(6): 3000605211014989, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34167351

RESUMO

OBJECTIVE: To investigate the anticancer effect of nelfinavir (NFV) on human A549 cells. METHODS: The inhibitory effects of NFV on the proliferation of human A549 cells were assessed using a MTT assay. Apoptotic cells were observed by fluorescence microscopy following Hoechst 33342 staining. Apoptosis of A549 cells was assessed using Annexin-V/propidium iodide staining and flow cytometry. Expression levels of signal transducer and activator of transcription 3 (STAT3) and p-STAT3 were measured by western blotting. STAT3 RNA silencing was used to investigate the pro-apoptotic mechanism of NFV in A549 cells. RESULTS: NFV dose-dependently suppressed proliferation of human A549 cells and induced significant apoptosis. Western blotting showed that the antitumor function of NFV might be mediated by STAT3 inhibition. A549 cell apoptosis in response to 20 µM NFV was significantly increased following STAT3 silencing. NFV significantly impeded the expression of the anti-apoptotic proteins Bcl-xL and Bcl-2, by increased the expression of the pro-apoptotic protein Cle-PARP. CONCLUSIONS: Our findings highlight STAT3 as a promising therapeutic target. NFV is a novel anti-cancer drug for the treatment of non-small-cell lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Células A549 , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Nelfinavir/farmacologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
14.
Acta Biochim Biophys Sin (Shanghai) ; 53(8): 1098-1105, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34169322

RESUMO

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling promotes tumorigenesis and cancer progression. STAT3 participates in the essential processes of cell proliferation, survival, and differentiation in many types of tumors. In the present study, SP2509 was identified as a potent inhibitor of the JAK/STAT3 signaling pathway by high-throughput drug screening based on a STAT3-driven luciferase expression system. Our results indicated that SP2509 inhibits constitutive STAT3 activation and the expression of STAT3-driven downstream genes. Bcl-xL, c-Myc, and Cyclin D1 were downregulated after treatment with SP2509. In addition, SP2509 specifically inhibits JAK activity, which could cause cell cycle arrest, inhibit cell growth, and induce apoptosis of various cancer cells. These results confirmed that SP2509 inhibits tumor progression by suppressing the expression of JAK/STAT3 signaling and STAT3-related downstream genes. Moreover, we demonstrated that SP2509 inhibits tumor growth in vivo and induces cell death in vitro. SP2509-mediated inhibition of STAT3 phosphorylation is dependent on its original target lysine-specific demethylase 1 in cancer cells. In summary, our results indicate that SP2509 is a novel inhibitor of JAK/STAT3 signaling.


Assuntos
Antineoplásicos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Hidrazinas/farmacologia , Proteínas de Neoplasias , Neoplasias/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Células A549 , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Janus Quinases/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética
15.
Eur J Med Chem ; 222: 113564, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34091208

RESUMO

COX-2 and STAT3 are two key culprits in the glioma microenvironment. Herein, to inhibit COX-2 and block STAT3 signaling, we disclosed 27 N-anthraniloyl tryptamine compounds based on the combination of melatonin derivatives and N-substituted anthranilic acid derivatives. Among them, NP16 showed the best antiproliferative activity and moderate COX-2 inhibition. Of note, NP16 decreased the level of p-JAK2 and p-STAT3, and blocked the nuclear translocation of STAT3 in GBM cell lines. Moreover, NP16 downregulated the MMP-9 expression of BV2 cells in a co-culture system of BV2 and C6 glioma cells, abrogated the proliferative/invasive/migratory abilities of GBM cells, induced apoptosis by ROS and the Bcl-2-regulated apoptotic pathway, and induced obvious G2/M arrest in glioma cells in vitro. Furthermore, NP16 displayed favorable pharmacokinetic profiles covering long half-life (11.43 ± 0.43 h) and high blood-brain barrier permeability. Finally, NP16 effectively inhibited tumor growth, promoted the survival rate, increased the expression of E-cadherin and reduced overproduction of PGE2, MMP-9, VEGF-A and the level of p-STAT3 in tumor tissue, and improved the anxiety-like behavior in C6 glioma model. All these evidences demonstrated N-anthraniloyl tryptamine derivatives as multifunctional anti-glioma agents with high potency could drain the swamp to beat glioma.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Glioma/tratamento farmacológico , Triptaminas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioma/metabolismo , Glioma/patologia , Humanos , Estrutura Molecular , Ratos , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/química , Células Tumorais Cultivadas
16.
Theranostics ; 11(14): 7029-7044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093869

RESUMO

Background: Increased IL-6 level, M2 macrophages and PD-1+CD8+ T cells in tumor microenvironments (TME) have been identified to correlate with resistance to checkpoint blockade immunotherapy, yet the mechanism remains poorly understood. Rab small GTPase-mediated trafficking of cytokines is critical in immuno-modulation. We have previously reported dysregulation of Rab37 in lung cancer cells, whereas the roles of Rab37 in tumor-infiltrating immune cells and cancer immunotherapy are unclear. Methods: The tumor growth of the syngeneic mouse allograft in wild type or Rab37 knockout mice was analyzed. Imaging analyses and vesicle isolation were conducted to determine Rab37-mediated IL-6 secretion. STAT3 binding sites at PD-1 promoter in T cells were identified by chromatin immunoprecipitation assay. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37, IL-6 and PD-1 and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from lung cancer patients. Results: We revealed that Rab37 regulates the secretion of IL-6 in a GTPase-dependent manner in macrophages to trigger M2 polarization. Macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells. Clinically, tumors with high stromal Rab37 and IL-6 expression coincide with tumor infiltrating M2-macrophages and PD1+CD8+ T cells that predicts poor prognosis in lung cancer patients. In addition, lung cancer patients with an increase in plasma IL-6 level are found to be associated with immunotherapeutic resistance. Importantly, combined blockade of IL-6 and CTLA-4 improves survival of tumor-bearing mice by reducing infiltration of PD1+CD8+ T cells and M2 macrophages in TME. Conclusions: Rab37/IL-6 trafficking pathway links with IL-6/STAT3/PD-1 transcription regulation to foster an immunosuppressive TME and combined IL-6/CTLA-4 blockade therapy exerts potent anti-tumor efficacy.


Assuntos
Interleucina-6/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral/imunologia , Proteínas rab de Ligação ao GTP/metabolismo , Aloenxertos , Animais , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica , Prognóstico , Receptor de Morte Celular Programada 1/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Microambiente Tumoral/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/ultraestrutura
17.
Life Sci ; 282: 119762, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34186047

RESUMO

AIMS: Radiofrequency ablation (RFA) is the first-line option for early-stage hepatocellular carcinoma (HCC). However, the residual tumor attributed to insufficient RFA (iRFA) led to tumor recurrence and metastasis. Novel combination strategies are urgently needed to enhance efficiency of RFA. MAIN METHODS: For in vitro iRFA models, HCC cells were placed in a water bath at 46 °C for 10 min and then returned to the original incubator. For in vivo models, HCC cells were implanted subcutaneously into nude mice. The nude mice were then randomly assigned into 4 groups: control group, XL888 group, iRFA group, combination of XL888 and iRFA group. CCK8 was performed to detect cell viability; Hoechst 33258 was used to explore nuclear morphology; The expression levels of proteins were demonstrated by western blotting; Co-localization of HSP90 and STAT3 was elucidated by immunofluorescence confocal microscopy; Immunohistochemistry was used to explore expression levels of proteins at tissue level. KEY FINDINGS: XL888 promoted apoptosis of HCC cells induced by heat via inhibiting expression levels of Mcl-1 and cleaved-caspase 3 in vivo and in vitro. XL888 attenuated the complex formation of HSP90 and STAT3, leading to decreased expression levels of STAT3 and p-STAT3. In human HCC tissues, IHC scores of HSP90 were positively correlated with those of STAT3. Overexpression of STAT3 rescued cell apoptosis induced by co-treatment of XL888 and heat. SIGNIFICANCE: We implied that XL888 promoted apoptosis of HCC cells induced by heat via disrupting the binding of HSP90 and STAT3, providing theoretical basis for a novel combination strategy for HCC.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Azabicíclicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Ácidos Ftálicos/farmacologia , Fator de Transcrição STAT3/genética , Animais , Compostos Azabicíclicos/uso terapêutico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Camundongos Endogâmicos BALB C , Camundongos Nus , Ácidos Ftálicos/uso terapêutico , Ablação por Radiofrequência
18.
Mol Cell Biochem ; 476(10): 3745-3756, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34100174

RESUMO

Sepsis is one of the leading causes of morbidity and mortality and a major cause of acute lung injury (ALI). carried by exosomes play a role in a variety of diseases. However,there are not many studies of exosomal miRNAs in sepsis and sepsis lung injury.miR-1298-5p and suppressor of cytokine signaling 6 (SOCS6) were silenced or overexpressed in human bronchial epithelial cells (BEAS-2B). PKH-67 Dye was used to trace exosome endocytosis. Cell permeability was evaluated by measuring trans-epithelial electrical resistance (TEER) and FITC dextran flux. ELISA kits were used for cytokine detection. Quantitative RT-PCR and western blots were used to evaluate gene expression. miR-1298-5p was elevated in exosomes from patients with sepsis lung injury (Sepsis_exo). Treatment of BEAS-2B cells using Sepsis_exo significantly inhibited cell proliferation, and induced cell permeability and inflammatory response. miR-1298-5p directly targeted SOCS6. Overexpressing SOCS6 reversed miR-1298-5p-induced cell permeability and inflammatory response. Inhibition of STAT3 blocked SOCS6-silencing caused significant increase of cell permeability and inflammation. Exosomes isolated from patients of sepsis lung injury increased cell permeability and inflammatory response in BEAS-2B cells through exosomal miR-1298-5p which targeted SOCS6 via STAT3 pathway. The findings highlight the importance of miR-1298-5p/SOCS6/STAT3 axis in sepsis lung injury and provide new insights into therapeutic strategies for sepsis lung injury.


Assuntos
Lesão Pulmonar Aguda/metabolismo , MicroRNAs/metabolismo , Sepse/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Lesão Pulmonar Aguda/genética , Linhagem Celular , Exocitose/genética , Exossomos/metabolismo , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Sepse/genética , Proteínas Supressoras da Sinalização de Citocina/genética
19.
Aging (Albany NY) ; 13(12): 16667-16683, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34165442

RESUMO

IL-6 is reported to be the main upstream activator, instead of the downstream target of JAK2/STAT3. This study is intended to explore the correlation of IL-6 and JAK2/STAT3 signaling pathway with clinicopathological features and prognosis in nasopharyngeal carcinoma (NPC). First, NPC tissues and normal nasopharyngeal epithelial tissues were obtained from 117 NPC patients. Next, we detected expression levels of IL-6 in serum and those of STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1 in tissues. A follow-up was conducted in all the patients and the survival was analyzed. To verify the correlation of IL-6 and JAK2/STAT3 pathway, CNE-1 and SUNE1 NPC cells were interpreted with IL-6 and JAK2/STAT3 signaling pathway inhibitor AG490 to detect cell viability, migration and invasion. We observed thatIL-6 increased in serum of NPC patients. The expressions of IL-6, STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1 in NPC tissues were higher and correlated with TNM stage and lymph node metastasis (LNM). Survival rates were reduced in patients with positive expressions of IL-6, STAT3, p-STAT3, JAK2, p-JAK2 and CyclinD1. LNM and positive expressions of IL-6 and p-STAT3 were risk factors for poor prognosis of NPC. Besides, recombinant human IL-6 promoted cell proliferation, invasion and migration while AG490 inhibited cell proliferation, invasion and migration in CNE-1 and SUNE1 NPC cells. The results demonstrated that increased IL-6 expression and the activated JAK2/STAT3 signaling pathway had effects on prognosis and reduced the survival time in NPC patients, which provide a potential target for the treatment of NPC.


Assuntos
Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Adolescente , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/genética , Janus Quinase 2/genética , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Invasividade Neoplásica , Fosforilação , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Fator de Transcrição STAT3/genética , Análise de Sobrevida , Regulação para Cima/genética , Adulto Jovem
20.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068421

RESUMO

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) is a major obstacle in managing lung cancer. The root of Scutellaria baicalensis (SB) traditionally used for fever clearance and detoxification possesses various bioactivities including anticancer effects. The purpose of this study was to investigate whether SB exhibited anticancer activity in EGFR TKI-resistant lung cancer cells and to explore the underlying mechanism. We used four types of human lung cancer cell lines, including H1299 (EGFR wildtype; EGFR TKI-resistant), H1975 (acquired TKI-resistant), PC9/ER (acquired erlotinib-resistant), and PC9/GR (acquired gefitinib-resistant) cells. The ethanol extract of SB (ESB) decreased cell viability and suppressed colony formation in the four cell lines. ESB stimulated nuclear fragmentation and the cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-3. Consistently, the proportion of sub-G1 phase cells and annexin V+ cells were significantly elevated by ESB, indicating that ESB induced apoptotic cell death in EGFR TKI-resistant cells. ESB dephosphorylated signal transducer and activator of transcription 3 (STAT3) and downregulated the target gene expression. The overexpression of constitutively active STAT3 reversed ESB-induced apoptosis, suggesting that ESB triggered apoptosis in EGFR TKI-resistant cells by inactivating STAT3. Taken together, we propose the potential use of SB as a novel therapeutic for lung cancer patients with EGFR TKI resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Extratos Vegetais/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Scutellaria baicalensis/química , Apoptose , Proliferação de Células , Receptores ErbB/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Raízes de Plantas/química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células Tumorais Cultivadas
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