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1.
Eur J Cancer ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34462189

RESUMO

BACKGROUND: GLS-010 (zimberelimab) is a novel, fully human, anti-programmed death-1 monoclonal antibody that shows promising efficacy and safety in advanced solid tumors. This trial aimed to evaluate the efficacy and safety of GLS-010 (zimberelimab) in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r-cHL). METHODS: This phase II, single-arm, open-label, multicenter clinical trial was conducted at 24 centers in China and enrolled patients with r/r-cHL after two or more lines of therapy. The patients were administered intravenous GLS-010 (zimberelimab) (240 mg, once every 2 weeks) until progression, death, unacceptable toxicity, or consent withdrawal. The primary end-point was the objective response rate assessed by an independent radiology review committee (IRC). This study was registered (NCT03655483). RESULTS: Eighty-five patients were enrolled between August 2018 and August 2019. The median follow-up was 15.8 months. Seventy-seven patients (90.6%; 95% confidence interval [CI] 82.3-95.9) had an IRC-assessed objective response. The complete response rate was 32.9% (n = 28). The 12-month progression-free survival and overall survival rates were 78% (95% CI 67.5-85.6) and 99% (95% CI 91.9-99.8), respectively. Treatment-related adverse events (TRAEs) were observed in 92.9% of participants. Grade III or IV TRAEs occurred in 24 (28.2%) of the 85 participants. The most common grade III or IV TRAEs were abnormal hepatic function (5.9%), hyperuricemia (4.7%), decreased neutrophil count (3.5%), and increased weight (3.5%). Only one grade V AE, gastrointestinal infection, occurred. CONCLUSIONS: GLS-010 (zimberelimab) appears to be effective and safe for the treatment of Chinese patients with r/r-cHL. Long-term follow-up is required to confirm these clinical benefits.

2.
Oxid Med Cell Longev ; 2021: 5481228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457114

RESUMO

Peripheral nerve injury (PNI), resulting in the impairment of myelin sheaths and axons, seriously affects the transmission of sensory or motor nerves. Growth factors (GFs) provide a biological microenvironment for supporting nerve regrowth and have become a promising alternative for repairing PNI. As one number of intracellular growth factor family, fibroblast growth factor 13 (FGF13) was regard as a microtubule-stabilizing protein for regulating cytoskeletal plasticity and neuronal polarization. However, the therapeutic efficiency and underlying mechanism of FGF13 for treating PNI remained unknown. Here, the application of lentivirus that overexpressed FGF13 was delivered directly to the lesion site of transverse sciatic nerve for promoting peripheral nerve regeneration. Through behavioral analysis and histological and ultrastructure examinations, we found that FGF13 not only facilitated motor and sense functional recovery but also enhanced axon elongation and remyelination. Furthermore, pretreatment with FGF13 also promoted Schwann cell (SC) viability and upregulated the expression cellular microtubule-associated proteins in vitro PNI model. These data indicated FGF13 therapeutic effect was closely related to maintain cellular microtubule stability. Thus, this work provides the evident that FGF13-medicated microtubule stability is necessary for promoting peripheral nerve repair following PNI, highlighting the potential therapeutic value of FGF13 on ameliorating injured nerve recovery.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Microtúbulos/química , Regeneração Nervosa , Neurônios/citologia , Traumatismos dos Nervos Periféricos/terapia , Recuperação de Função Fisiológica , Células de Schwann/citologia , Animais , Fatores de Crescimento de Fibroblastos/genética , Masculino , Neurônios/fisiologia , Traumatismos dos Nervos Periféricos/etiologia , Traumatismos dos Nervos Periféricos/patologia , Ratos , Ratos Sprague-Dawley , Células de Schwann/fisiologia
3.
Eur J Cancer ; 148: 1-13, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33691262

RESUMO

BACKGROUND: GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. AIM: This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. METHODS: In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. RESULTS: Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response. CONCLUSION: GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.

4.
Behav Brain Res ; 407: 113261, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33775778

RESUMO

Neuronal loss has been identified in depression, but its mechanisms are not fully understood. Proteomic analyses provide a novel insight to explore the potential mechanisms of such pathological alterations. In this study, mice were treated with chronic unpredictable mild stress (CUMS) for 2 months to establish depression models. The hippocampus was analyzed for proteomic patterns by mass spectrometry followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Behavioral tests showed that mice receiving CUMS showed depression-like symptoms such as anhedonia in the sucrose preference test (SPT) and behavioral despair in the forced swimming test (FST). CUMS induced anxiety-like behaviors in the open field test (OFT), but did not impair spatial learning and memory ability in the Morris water maze (MWM) test. Out of 4046 quantified proteins, 47 differentially expressed proteins were obtained between the CUMS and control groups. These proteins were functionally enriched in a series of biological processes. Among the notably enriched pathways, necroptosis and ferroptosis were significantly activated. Western blot and biochemical assay analyses identified changes in receptor-interacting protein kinase 3 (RIP3), phosphorylated mixed lineage kinase domain-like protein (p-MLKL), ferritin light chain 1 (Ftl1) and lipid peroxidation that were related to necroptosis and ferroptosis. Further, we found reduced levels of alpha-crystallin B (Cryab) and brain-derived neurotrophic factor (BDNF), which were also associated with neuronal survival. Our study highlighted that necroptosis and ferroptosis were involved in depression and partially account for neuronal loss, thereby providing potentially novel targets for the treatment of depression.

5.
Aging (Albany NY) ; 13(3): 3386-3404, 2021 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-33428605

RESUMO

In this study, we investigated the role of tumor-associated macrophages (TAMs) in the progression of pancreatic ductal adenocarcinoma (PDAC). PDAC patients with higher levels of CD68+ TAMs exhibited shorter overall survival. In Transwell assays, PDAC cells incubated with TAMs or conditioned media from TAM cells (TAM-CM) showed higher migration and invasion rates than controls. PET/CT scan analysis of orthotopic PDAC model mice revealed greater primary tumor growth and liver metastasis in the TAM-CM treatment group than the controls. H&E staining of liver tissues showed significantly higher numbers of metastatic nodules in the TAM-CM treatment group. Heat inactivation of TAM-CM significantly reduced Transwell migration by PDAC cells, suggesting the involvement of one or more secreted proteins in PDAC progression. Transcriptome sequencing analysis of PDAC cells treated with TAM-CM revealed significant enrichment of transforming growth factor-ß (TGF-ß) signaling pathway genes. Western blot and qRT-PCR analysis showed that TAM-CM enhanced PDAC migration cells by inducing epithelial-to-mesenchymal transition through the TGF-ß-Smad2/3/4-Snail signaling axis. The pro-tumorigenic effects of TAMs or TAM-CM were abolished by TGF-ß signaling pathway inhibitors and neutralizing TGF-ß antibody. These results demonstrate that TAMs promote PDAC progression through the TGF-ß signaling pathway.


Assuntos
Carcinoma Ductal Pancreático/imunologia , Transição Epitelial-Mesenquimal/imunologia , Neoplasias Pancreáticas/imunologia , Macrófagos Associados a Tumor/imunologia , Animais , Carcinoma Ductal Pancreático/secundário , Linhagem Celular Tumoral , Movimento Celular , Meios de Cultivo Condicionados , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Camundongos , Invasividade Neoplásica , Transplante de Neoplasias , Neoplasias Pancreáticas/patologia , Prognóstico , Proteína Smad2/imunologia , Proteína Smad3/imunologia , Proteína Smad4/imunologia , Fatores de Transcrição da Família Snail/imunologia , Células THP-1 , Fator de Crescimento Transformador beta/imunologia
6.
J Cell Mol Med ; 25(5): 2596-2608, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33512767

RESUMO

The successful removal of damaged myelin sheaths during Wallerian degeneration (WD) is essential for ensuring structural remodelling and functional recovery following traumatic peripheral nerve injury (PNI). Recent studies have established that autophagy involves myelin phagocytosis and cellular homoeostasis, and its disorder impairs myelin clearance. Based on the role of basic fibroblast growth factor (bFGF) on exerting neuroprotection and angiogenesis during nerve tissue regeneration, we now explicitly focus on the issue about whether the therapeutic effect of bFGF on supporting nerve regeneration is closely related to accelerate the autophagic clearance of myelin debris during WD. Using sciatic nerve crushed model, we found that bFGF remarkedly improved axonal outgrowth and nerve reconstruction at the early phase of PNI (14 days after PNI). More importantly, we further observed that bFGF could enhance phagocytic capacity of Schwann cells (SCs) to engulf myelin debris. Additionally, this enhancing effect is accomplished by autophagy activation and the increase of autophagy flux by immunoblotting and immune-histochemical analyses. Taken together, our data suggest that the action of bFGF on modulating early peripheral nerve regeneration is closely associated with myelin debris removal by SCs, which might result in SC-mediated autophagy activation, highlighting its insight molecular mechanism as a neuroprotective agent for repairing PNI.


Assuntos
Autofagia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Bainha de Mielina/metabolismo , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/metabolismo , Animais , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Imuno-Histoquímica , Masculino , Regeneração Nervosa/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/etiologia , Traumatismos dos Nervos Periféricos/patologia , Fagocitose , Ratos , Células de Schwann/metabolismo , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia
7.
Int J Mol Med ; 47(2): 463-474, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33416123

RESUMO

Recently, the increasing emergency of traffic accidents and the unsatisfactory outcome of surgical intervention are driving research to seek a novel technology to repair traumatic soft tissue injury. From this perspective, decellularized matrix grafts (ECM­G) including natural ECM materials, and their prepared hydrogels and bioscaffolds, have emerged as possible alternatives for tissue engineering and regenerative medicine. Over the past decades, several physical and chemical decellularization methods have been used extensively to deal with different tissues/organs in an attempt to carefully remove cellular antigens while maintaining the non­immunogenic ECM components. It is anticipated that when the decellularized biomaterials are seeded with cells in vitro or incorporated into irregularly shaped defects in vivo, they can provide the appropriate biomechanical and biochemical conditions for directing cell behavior and tissue remodeling. The aim of this review is to first summarize the characteristics of ECM­G and describe their major decellularization methods from different sources, followed by analysis of how the bioactive factors and undesired residual cellular compositions influence the biologic function and host tissue response following implantation. Lastly, we also provide an overview of the in vivo application of ECM­G in facilitating tissue repair and remodeling.


Assuntos
Materiais Biocompatíveis , Matriz Extracelular/química , Hidrogéis , Engenharia Tecidual , Tecidos Suporte/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/uso terapêutico , Humanos , Hidrogéis/química , Hidrogéis/uso terapêutico
8.
Int J Biol Sci ; 17(1): 107-118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33390837

RESUMO

Aerobic glycolysis, also known as the Warburg effect, is emerged as a hallmark of most cancer cells. Increased aerobic glycolysis is closely associated with tumor aggressiveness and predicts a poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is characterized by prominent genomic aberrations and increased glycolytic phenotype. However, the detailed molecular events implicated in aerobic glycolysis of PDAC are not well understood. In this study, we performed a comprehensive molecular characterization using multidimensional ''omic'' data from The Cancer Genome Atlas (TCGA). Detailed analysis of 89 informative PDAC tumors identified substantial copy number variations (MYC, GATA6, FGFR1, IDO1, and SMAD4) and mutations (KRAS, SMAD4, and RNF43) related to aerobic glycolysis. Moreover, integrated analysis of transcriptional profiles revealed many differentially expressed long non-coding RNAs involved in PDAC aerobic glycolysis. Loss-of-function studies showed that LINC01559 and UNC5B-AS1 knockdown significantly inhibited the glycolytic capacity of PDAC cells as revealed by reduced glucose uptake, lactate production, and extracellular acidification rate. Moreover, genetic silencing of LINC01559 and UNC5B-AS1 suppressed tumor growth and resulted in alterations in several signaling pathways, such as TNF signaling pathway, IL-17 signaling pathway, and transcriptional misregulation in cancer. Notably, high expression of LINC01559 and UNC5B-AS1 predicted poor patient prognosis and correlated with the maximum standard uptakevalue (SUVmax) in PDAC patients who received preoperative 18F-FDG PET/CT. Taken together, our results decipher the glycolysis-associated copy number variations, mutations, and lncRNA landscapes in PDAC. These findings improve our knowledge of the molecular mechanism of PDAC aerobic glycolysis and may have practical implications for precision cancer therapy.

9.
Transpl Immunol ; 65: 101357, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33279598

RESUMO

BACKGROUND: Mycophenolate mofetil (MMF), an immunosuppressive drug, exerts anti-inflammatory effects on organs during ischemia/reperfusion (I/R) injury. However, the exact function of MMF in hepatic I/R injury remains largely unknown. The purpose of this study was to explore the role and potential mechanism of MMF protection in hepatic I/R injury. METHODS: Male wild type (WT) and TLR4 knockout (KO) mice were injected intraperitoneally with MMF or normal saline. Animals underwent 90 min of partial hepatic ischemia, followed by 1, 6, or 24 h of reperfusion. Hepatic histology, serum amiotransferase, inflammatory cytokines, hepatocyte apoptosis, and hepatocyte autophagy were examined to assess liver injury. RESULTS: Treatment with MMF significantly decreased hepatic I/R injury as indicated by a reduction in serum aminotransferase levels, Suzuki scores, and the overall degree of necrosis. MMF treatment inhibited TLR4 activation dramatically. MMF administration also significantly inhibited the activation of the NF-κB pathway and the expression of pro-inflammatory cytokines. In TLR4 KO mice, MMF still exerted protection from hepatic I/R injury. MMF treatment inhibited hepatocyte apoptosis, as indicated by reduced TUNEL staining, and reduced the accumulation of cleaved caspase-3. In addition, MMF may induce autophagy and increase autophagic flux before and after hepatic reperfusion by augmenting the expression of LC3-II, P62, and Beclin-1. The induction of autophagy by MMF treatment may be related to TLR4 activation. CONCLUSIONS: Our results indicate that MMF treatment ameliorates hepatic I/R injury. The mechanism of action likely involves the ability of MMF to decrease apoptosis and the inflammatory response while inducing autophagy.

10.
Front Psychiatry ; 11: 575705, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33250791

RESUMO

Background: The outbreak of coronavirus disease 2019 in Wuhan, Hubei Province, China has seriously affected people's mental health. We aimed to assess the psychological impact of the coronavirus disease 2019 on health care workers and non-health care workers in three different epidemic areas in China and to identify independent risk factors. Methods: We surveyed 1,020 non-health care workers and 480 health care workers in Wuhan, other cities in Hubei except Wuhan and other provinces in China except Hubei. Results: Health care workers in Hubei had higher levels of anxiety and depression than non-health care workers (p < 0.05), but there was no such difference in other provinces in China except Hubei (p > 0.05). Compared with other regions, health care workers in Wuhan was more anxious (p < 0.05), and this anxiety may be caused by concerns about occupational exposure and wearing protective clothing for a long time daily; health care workers in Hubei had more obvious depression (p < 0.05), which may be associated with long days participating in epidemic work and wearing protective clothing for a long time daily. Meanwhile, 62.5% of health care workers were proud of their work. The anxiety and depression of non-health care workers in Wuhan were also the most serious. Conclusions: In Wuhan, where the epidemic is most severe, levels of anxiety and depression seem to be higher, especially among health care workers. This information may help to better prepare for future events.

11.
Nutr Cancer ; : 1-13, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33225744

RESUMO

Lung cancer is one of the common types of malignant disorders and the most prevalent cause of cancer-related mortality in the world. Although a wide range of approaches has been examined, strategies in prevention and treatment of lung cancer are still inadequate. Studies show that Vitamin D (VitD) is involved in various biological pathways and has been associated with the etiopathogenesis of several diseases, like cancers. In Vitro and In Vivo experiments have disclosed that VitD plays immunomodulatory and anti-tumor functions. Several lines of evidence have indicated that VitD is involved in the inflammatory settings of the lung. Epidemiological studies have reported that sufficient levels of VitD might be critical in the prevention of lung cancer. Polymorphisms in the genes encoding the different molecules involved in the signaling of VitD might affect the lung cancer risk as well as the quality and quantity of responses to different treatments. In this review article, we intended to clarify the implications of VitD in the normal biology and physiology of the lung and discuss diverse line of evidence about the possible role of VitD in the prevention or treatment of lung cancer.

12.
J Psychiatr Res ; 125: 152-163, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32289652

RESUMO

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is widely used to treat depression. However, the underlying mechanism has not been identified, and there is uncertainty regarding the optimal choice of stimulus parameters, especially stimulus frequency. Our previous study in mice demonstrated that 10-Hz HF-rTMS ameliorated depression by inducing expression of Homer1a and reducing excitability of cortical pyramidal cells. The aims of this study were to compare the effects of 15-Hz and 25-Hz HF-rTMS in a model of chronic unpredictable mild stress (CUMS)-induced depression and investigate its possible molecular mechanism. Male C57BL/6J mice were treated with CUMS for 28 days followed by 15-Hz and 25-Hz rTMS for 4 weeks. The sucrose preference, open field, forced swimming, and tail suspension tests were used to evaluate depression-like behaviors. Immunostaining was performed to measure neuronal loss and neurogenesis. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. Expression of synapse-related proteins and the effects of HF-rTMS on the signaling pathway were examined using Western blot. The results showed that both 15-Hz and 25-Hz rTMS had significant antidepressant effects; 15-Hz rTMS seemed to be more effective than 25-Hz rTMS in preventing neuronal loss and promoting neurogenesis, while 25-Hz rTMS was superior to 15-Hz rTMS in facilitating synaptic plasticity. We also found that 15-Hz and 25-Hz rTMS markedly increased expression of p11, BDNF, Homer1a, and p-trkB proteins. These findings suggest that 15-Hz and 25-Hz HF-rTMS could exert neuroprotective effects to different degrees via multiple perspectives, which at least in part involve the p11/BDNF/Homer1a pathway.


Assuntos
Depressão , Estimulação Magnética Transcraniana , Animais , Fator Neurotrófico Derivado do Encéfalo , Depressão/etiologia , Depressão/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
13.
Cancer Res ; 80(10): 1991-2003, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32098780

RESUMO

Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8+ T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8+ T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8+ T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8+ T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion-triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8+ T-cell infiltration and a reduced Th1/Th2 ratio. SIGNIFICANCE: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion.


Assuntos
Acetilcolina/metabolismo , Carcinoma Ductal Pancreático/patologia , Invasividade Neoplásica/imunologia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/imunologia , Animais , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Humanos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/fisiologia
14.
Cell Death Dis ; 10(12): 948, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31827081

RESUMO

Hypoxia and the hypovascular tumor microenvironment are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is of great importance to tumor survival and proliferation. There is little research regarding the role of Nuclear Factor of Activated T Cells 5 (NFAT5) in relation to carcinoma. Here, we explored the impact of NFAT5 on the biological behavior of PDAC and the underlying mechanism. We demonstrated that NFAT5 was highly expressed in PDAC and was related to poorer prognosis. Knockdown of NFAT5 lead to impaired proliferation of tumor cells caused by an aberrant Warburg effect. Mechanically, phosphoglycerate kinase 1 (PGK-1), which is the first enzyme generating ATP in glycolysis, was verified as a target gene of NFAT5. Over-expression of PGK1 compromised the aberrant oncological behavior caused by knockdown of NFAT5 both in vitro and in vivo. Clinical samples underwent positron emission tomography-computed tomography (PET-CT) examination and KrasG12D/+/Trp53R172H/+/Pdx1-Cre (KPC) mice were collected to support our conclusion.


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Fosfoglicerato Quinase/genética , Fatores de Transcrição/genética , Transcrição Genética , Adenocarcinoma/patologia , Idoso , Animais , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glicólise/genética , Xenoenxertos , Proteínas de Homeodomínio/genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/genética , Transativadores/genética , Hipóxia Tumoral/genética , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética
15.
J Immunol Res ; 2019: 8656282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583260

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating cancer types despite the improvement of modern medicine. In our present study, we found that dickkopf-related protein 2 (DKK2) shares a higher expression in PDAC compared with adjacent pancreas tissue in tissue microarray. In addition, an elevated expression of DKK2 predicts poorer prognosis of patients and positively correlated with poor tumor differentiation. Multivariate Cox regression analysis was also performed and confirmed that the expression of DKK2 is an independent prognostic factor in PDAC. A high expression of DKK2 correlates with cell migration and epithelial mesenchymal transition based on gene set enrichment analysis (GSEA) while knockdown of DKK2 in PDAC cells resulted in impaired cellular migration. Furthermore, GSEA predicts negative correlation between tumor immunity invasion and DKK2 expression. We then confirmed these results and demonstrated that a higher expression of DKK2 imparts the recruitment of CD8+ T cells. Our work suggested that DKK2 imparts tumor immune evasion and is associated with poor prognosis in pancreatic ductal adenocarcinoma.


Assuntos
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Adulto , Idoso , Biomarcadores Tumorais , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Análise de Sobrevida , Via de Sinalização Wnt
16.
World J Gastroenterol ; 25(14): 1684-1696, 2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-31011254

RESUMO

BACKGROUND: Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas (G-NECs) remains unknown. AIM: To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant. METHODS: We investigated the expression of PD-L1 on tumor cells and PD-1+, CD8+, and FOXP3+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR. RESULTS: Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43 G-NECs, 21 (48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival (OS). The high expression of PD-L1 was correlated with abundant PD-1+ tumor infiltrating lymphocytes (TILs) instead of CD8+ TILs and FOXP3+ regulatory T cells (Tregs). Our analysis also suggested that the infiltration of CD8+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance (P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without. CONCLUSION: Our data demonstrated for the first time that high expression of PD-L1 in G-NECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in G-NECs.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Neuroendócrino/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/imunologia , Neoplasias Gástricas/imunologia , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Variações do Número de Cópias de DNA , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Evasão Tumoral/imunologia
17.
Gut ; 68(11): 1994-2006, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30826748

RESUMO

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis. METHODS: The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism. RESULTS: GABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression. CONCLUSIONS: Overexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Quimiocinas/metabolismo , Modelos Animais de Doenças , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Macrófagos/fisiologia , Camundongos , Transdução de Sinais/fisiologia
18.
Am J Cancer Res ; 9(2): 363-377, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906634

RESUMO

Secreted Frizzled-Related Protein 4 (SFRP4), a member of secreted frizzled-related protein family, has been found as a vital modulator in cell proliferation, cell self-renew and apoptosis through Wnt signaling transduction pathway. In the present study, we re-analyzed the expression pattern of SFRPs in Gene Expression Omnibus (GEO) datasets and evaluated the expression of SFRP4 at protein level in both KrasG12D/+; Trp53R172H/+; Pdx1-Cre; (KPC) mice and human pancreatic ductal adenocarcinoma (PDAC) tissue. We found that the expression of SFRP4 increased gradually in PanINs and PDAC lesions in KPC mice and high expression of SFRP4 was much more common in tumor lesions compared to the adjacent non-tumor tissues. Then we performed Kaplan-Meier survival and Cox regression analysis and found that high expression of SFRP4 in the serum and tumor lesions predicted poor prognosis for pancreatic cancer patients. Furthermore, we demonstrated that SFRP4 positively correlated with FOXP3+ Treg cells infiltration while the down-regulation of SFRP4 in tumor cells impaired the production of cytokines and the recruitments of T cells. This study suggested that SFRP4 can be a novel prognostic biomarker and potential therapeutic target for pancreatic cancer.

19.
Clin Cancer Res ; 25(4): 1318-1330, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30420446

RESUMO

PURPOSE: Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment. EXPERIMENTAL DESIGN: Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression. RESULTS: P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice. CONCLUSIONS: These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Glicólise/genética , Receptores Purinérgicos P2Y2/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Trifosfato de Adenosina/genética , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Evolução Clonal/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Elafina/genética , Glicólise/efeitos dos fármacos , Xenoenxertos , Humanos , Camundongos , Proteína Oncogênica v-akt/genética , Antagonistas do Receptor Purinérgico P2Y , RNA Interferente Pequeno/farmacologia , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Microambiente Tumoral/efeitos dos fármacos
20.
Sci Rep ; 8(1): 15792, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30361522

RESUMO

Due to the therapy resistance and frequent metastasis, pancreatic ductal adenocarcinoma(PDAC) remains one of the most malignant carcinoma. WNT7A, an important ligand of Wnt/ß-catenin signaling pathways, has a controversial role in tumor development. The role of WNT7A in PDAC remains unclear. In this study, we analyzed the expression pattern of WNT7A at mRNA and protein levels. We found pancreatic cancer tissue demonstrated a significant high WNT7A expression compared with the adjacent non-tumor tissue and the expression of WNT7A positively correlates with poor prognosis and lymph node metastasis. Then, we performed transwell assays and wound healing assays in vitro and found that WNT7A promotes the migration capacity of cancer cells. Furthermore, we explored the underlying mechanism of the WNT7A inducing cell migration. Results showed that up-regulated WNT7A expression inducing higher expression of N-cadherin and lower expression of E-cadherin while the contrast result was shown in the WNT7A knock-down group, which suggested that WNT7A might contribute to an epithelial-mesenchymal transition. Finally, we found that the hypoxia culture condition remarkably increased the WNT7A expression. In conclusion, our work demonstrated that hypoxia induced high expression of WNT7A might promote the cell migration via enhancing the epithelial-mesenchymal transition in PDAC.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas Wnt/genética , Hipóxia Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/genética , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/genética
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