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1.
Genes Genomics ; 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38064156

RESUMO

BACKGROUND: CDH3 is a glycoprotein with a single-span transmembrane domain that mediates cell-to-cell adhesion. Abnormal expression of CDH3 is associated with a poor prognosis in patients with breast, thyroid, colorectal carcinomas and glioblastoma. Soluble CDH3 in pleural effusions can be used as a marker for real-time monitoring of resistance to first- and second-generation EGFR-TKIs. The CDH3 mechanism underlying lung adenocarcinomas (LUADs) has not been established. OBJECTIVE: This study analyzed the correlation between CDH3 expression and lung cancer prognosis and the effect of down-regulation CDH3 expression on the proliferation and migration of lung cancer cells. METHODS: CDH3 expression was studied using the Oncomine, TIMER, PanglaoDB, and GEPIA databases. The effect of CDH3 on clinical prognosis was assessed with GEPIA, the PrognoScan database, and Kaplan-Meier plotter. The relationship between CDH3 to immune infiltrating cells was explored using TIMER and TISIDB. The function of CDH3 in lung cancer cell lines was determined by CCK-8 and wound healing assays in vitro. Furthermore, RNA sequencing was used to identify key signaling pathways and differentially-expressed genes. RESULTS: LUAD tissues had higher CDH3 expression compared with normal tissues and were associated with worse overall survival in patients with LUAD. CDH3 expression had positive associations with infiltration of CD4 + T cells, Tregs and exhausted T cells, but negative associations with infiltration of B cells in patients with LUAD. CCK-8 and wound healing assays revealed that downregulation of CDH3 inhibited the proliferation and migration of cells. KEGG analysis revealed that the TGF-beta signaling pathways were demonstrated to be enriched pathways for genes negatively regulated by knockdown of CDH3. CONCLUSION: CDH3 expression affects proliferation and migration of lung cancer cells and might serve as a potential prognostic marker in LUAD patients.

2.
Mol Med ; 29(1): 162, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38041015

RESUMO

BACKGROUND: The linear long non-coding RNA P14AS has previously been reported to be dysregulated in colon cancer, but the mechanistic role that P14AS plays in colon cancer progression has yet to be clarified. Accordingly, this study was developed to explore the regulatory functions of ANRIL linear transcript-P14AS in cancer. METHODS: The expression of P14AS, ANRIL, miR-23a-5p and their target genes were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell supernatants of IL6 and IL8 were measured by Enzyme linked immunosorbent (ELISA) assay. Dual-luciferase reporter assays, RNA immunoprecipitation, or pull-down assays were used to confirm the target association between miR-23a-5p and P14AS or UBE2D3. Cell proliferation and chemosensitivity of NF-κB inhibitor BAY 11-7085 were evaluated by cell counting kit 8 (CCK8). RESULTS: When P14AS was overexpressed in colon cancer cell lines, enhanced TNF-NF-κB signaling pathway activity was observed together with increases in IL6 and IL8 expression. The Pita, miRanda, and RNA hybrid databases revealed the ability of miR-23a-5p to interact with P14AS, while UBE2D3 was further identified as a miR-23a-5p target gene. The results of dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation experiments confirmed these direct interactions among P14AS/miR-23a-5p/UBE2D3. The degradation of IκBa mediated by UBE2D3 may contribute to enhanced NF-κB signaling in these cells. Moreover, the beneficial impact of P14AS on colon cancer cell growth was eliminated when cells were treated with miR-23a-5p inhibitors or UBE2D3 was silenced. As such, these findings strongly supported a role for the UBE2D3/IκBa/NF-κB signaling axis as a mediator of the ability of P14AS to promote colon cancer progression. CONCLUSIONS: These data suggested a mechanism through which the linear ANRIL transcript P14AS can promote inflammation and colon cancer progression through the sequestration of miR-23a-5p and the modulation of NF-κB signaling activity, thus highlighting P14AS as a promising target for therapeutic intervention efforts.


Assuntos
Neoplasias do Colo , MicroRNAs , Humanos , Proliferação de Células , Neoplasias do Colo/genética , Interleucina-6/genética , Interleucina-8/genética , Luciferases/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Processos Neoplásicos , NF-kappa B/metabolismo , Transdução de Sinais
3.
Food Funct ; 14(18): 8409-8419, 2023 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-37615035

RESUMO

Background: Depression is a psychiatric disorder with depressed mood and even suicide attempts as the main clinical symptoms, and its pathogenesis has not yet been fully elucidated. Brain derived neurotrophic factor (BDNF) plays an important role in the pathogenesis of depression. Purpose: The main aim of the present study was to evaluate the effectiveness and reveal the potential mechanisms of bilobalide (BB) intervention in alleviating depression-like behaviors by using chronic unpredictable mild stress (CUMS) mice via mediating the BDNF pathway. Methods: Behavioral assessments were carried out by using the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). CUMS mice were randomly divided into 5 groups: CUMS + solvent, CUMS + BB low, CUMS + BB medium, CUMS + BB high and CUMS + fluoxetine. Total serum levels of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) were measured by ELISA. Expression of TNF-α, IL-6, AKT, GSK3ß, ß-catenin, Trk-B and BDNF in the mouse hippocampus was assessed by western blotting. Results: BB treatment reduced the levels of pro-inflammatory cytokines (IL-6 and TNF-α) and increased the protein expression of BDNF in the hippocampus region of the CUMS mice. Moreover, BB treatment enhanced the AKT/GSK3ß/ß-catenin signaling pathway which is downstream of the BDNF receptor Trk-B in the hippocampus of these mice. Conclusions: Overall, the experimental results indicated that BB reverses CUMS-induced depression-like behavior. BB exerts antidepressant-like effects by inhibiting neuroinflammation and enhancing the function of neurotrophic factors.


Assuntos
Bilobalídeos , Fator Neurotrófico Derivado do Encéfalo , Animais , Camundongos , Fator Neurotrófico Derivado do Encéfalo/genética , Fator de Necrose Tumoral alfa/genética , Depressão/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta , Interleucina-6/genética , Proteínas Proto-Oncogênicas c-akt , beta Catenina
4.
Front Cell Dev Biol ; 10: 1062931, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36568974

RESUMO

[This corrects the article DOI: 10.3389/fcell.2022.993525.].

5.
Front Cell Dev Biol ; 10: 993525, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36176277

RESUMO

Background: It is well known that P16 INK4A , P14 ARF , P15 INK4B mRNAs, and ANRIL lncRNA are transcribed from the CDKN2A/2B locus. LncRNA P14AS is a lncRNA transcribed from antisense strand of P14 ARF promoter to intron-1. Our previous study showed that P14AS could upregulate the expression level of ANRIL and P16 INK4A and promote the proliferation of cancer cells. Because polycomb group protein CBX7 could repress P16 INK4A expression and bind ANRIL, we wonder whether the P14AS-upregulated ANRIL and P16 INK4A expression is mediated with CBX7. Results: In this study, we found that the upregulation of P16 INK4A , P14 ARF , P15 INK4B and ANRIL expression was induced by P14AS overexpression only in HEK293T and HCT116 cells with active endogenous CBX7 expression, but not in MGC803 and HepG2 cells with weak CBX7 expression. Further studies showed that the stable shRNA-knockdown of CBX7 expression abolished the P14AS-induced upregulation of these P14AS target genes in HEK293T and HCT116 cells whereas enforced CBX7 overexpression enabled P14AS to upregulate expression of these target genes in MGC803 and HepG2 cells. Moreover, a significant association between the expression levels of P14AS and its target genes were observed only in human colon cancer tissue samples with high level of CBX7 expression (n = 38, p < 0.05), but not in samples (n = 37) with low level of CBX7 expression, nor in paired surgical margin tissues. In addition, the results of RNA immunoprecipitation (RIP)- and chromatin immunoprecipitation (ChIP)-PCR analyses revealed that lncRNA P14AS could competitively bind to CBX7 protein which prevented the bindings of CBX7 to both lncRNA ANRIL and the promoters of P16 INK4A , P14 ARF and P15 INK4B genes. The amounts of repressive histone modification H3K9m3 was also significantly decreased at the promoters of these genes by P14AS in CBX7 actively expressing cells. Conclusions: CBX7 expression is essential for P14AS to upregulate the expression of P16 INK4A , P14 ARF , P15 INK4B and ANRIL genes in the CDKN2A/2Blocus. P14AS may upregulate these genes' expression through competitively blocking CBX7-binding to ANRIL lncRNA and target gene promoters.

6.
Aging (Albany NY) ; 14(7): 3155-3174, 2022 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-35398839

RESUMO

The biological functional network of tumor tissues is relatively stable for a period of time and under different conditions, so the impact of tumor heterogeneity is effectively avoided. Based on edge perturbation, functional gene interaction networks were used to reveal the pathological environment of patients with non-small cell carcinoma at the individual level, and to identify cancer subtypes with the same or similar status, and then a multi-dimensional and multi-omics comprehensive analysis was put into practice. Two edge perturbation subtypes were identified through the construction of the background interaction network and the edge-perturbation matrix (EPM). Further analyses revealed clear differences between those two clusters in terms of prognostic survival, stemness indices, immune cell infiltration, immune checkpoint molecular expression, copy number alterations, mutation load, homologous recombination defects (HRD), neoantigen load, and chromosomal instability. Additionally, a risk prediction model based on TCGA for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) was successfully constructed and validated using the independent data set (GSE50081).


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Humanos , Neoplasias Pulmonares/patologia , Prognóstico
7.
Nature ; 604(7904): 59-64, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35139530

RESUMO

Electronic nematicity, in which rotational symmetry is spontaneously broken by electronic degrees of freedom, has been demonstrated as a ubiquitous phenomenon in correlated quantum fluids including high-temperature superconductors and quantum Hall systems1,2. Notably, the electronic nematicity in high-temperature superconductors exhibits an intriguing entanglement with superconductivity, generating complicated superconducting pairing and intertwined electronic orders. Recently, an unusual competition between superconductivity and a charge-density-wave (CDW) order has been found in the AV3Sb5 (A = K, Rb, Cs) family with two-dimensional vanadium kagome nets3-8. Whether these phenomena involve electronic nematicity is still unknown. Here we report evidence for the existence of electronic nematicity in CsV3Sb5, using a combination of elastoresistance measurements, nuclear magnetic resonance (NMR) and scanning tunnelling microscopy/spectroscopy (STM/S). The temperature-dependent elastoresistance coefficient (m11 minus m12) and NMR spectra demonstrate that, besides a C2 structural distortion of the 2a0 × 2a0 supercell owing to out-of-plane modulation, considerable nematic fluctuations emerge immediately below the CDW transition (approximately 94 kelvin) and finally a nematic transition occurs below about 35 kelvin. The STM experiment directly visualizes the C2-structure-pinned long-range nematic order below the nematic transition temperature, suggesting a novel nematicity described by a three-state Potts model. Our findings indicate an intrinsic electronic nematicity in the normal state of CsV3Sb5, which sets a new paradigm for revealing the role of electronic nematicity on pairing mechanism in unconventional superconductors.

8.
Transfus Apher Sci ; 60(6): 103277, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34563458

RESUMO

OBJECTIVE: The goal of this study was to predict the probability of transfusion of red blood cells and the volume of blood consumption based on the clinical characteristics of patients before surgery. METHODS: The medical records of 565 patients over 65 years old who underwent posterior lumbar surgery and 586 patients over 65 years old receiving femoral fracture surgery were reviewed. The clinical characteristics of the patients were subjected to multivariate regression analysis. The scores of these factors' influences on intraoperative red blood cells infusion were based on the odds ratio of each multivariate risk factor. Non-linear regression was performed to predict the probability of intraoperative blood transfusion and the volume of blood used for patients with different scores. RESULTS: The factors that significantly influenced blood use during lumbar spinal stenosis and femoral fracture surgery in aged patients(P < 0.05) included age, body mass index, abnormal coagulation function, preoperative hemoglobin, administration of antithrombotic drugs, multisegmental lesions of the lumbar spine, femoral shaft fracture, secondary lumbar surgery and the time from fracture to surgery exceeding 48 h. According to our risk scoring system, patients of posterior lumbar surgery scored 0-10 and patients of femoral fracture had a score of 0-12. More than 50 % of patients receiving an intraoperative red blood cells transfusion during surgery scored>1. CONCLUSION: The scoring system can be used as a predictive model for the probability of red blood cells transfusion and the blood volume in aged patients undergoing lumbar spinal stenosis and femoral fracture surgeries.


Assuntos
Transfusão de Sangue/métodos , Fraturas do Fêmur/cirurgia , Fraturas do Fêmur/terapia , Estenose Espinal/cirurgia , Estenose Espinal/terapia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Probabilidade
9.
Ultrason Sonochem ; 78: 105707, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34388653

RESUMO

The aim of present study was to investigate the influences of ultrasound-assisted immersion freezing (UIF), immersion freezing (IF) and air freezing (AF) on the quality, moisture distribution and microstructure properties of the prepared ground pork (PGP) during storage duration (0, 15, 30, 45, 60, 75 and 90 days). UIF treatment significantly reduced the freezing time by 60.32% and 39.02%, respectively, compared to IF and AF (P < 0.05). The experimental results of quality evaluation revealed that the L* and b* values, juice loss, cooking loss, TBARS values and carbonyl contents were decreased in the UIF treated samples, while the a* value, peak temperatures (Tm), enthalpy (ΔH) and sulfhydryl contents were significantly higher than those of IF and AF treated samples (P < 0.05). In addition, low-field nuclear magnetic resonance (LF-NMR) and differential scanning calorimetry (DSC) analysis demonstrated that UIF inhibited the mobility of immobilized water and reduced the loss of immobilized and free water, and then a high water holding capacity (WHC) was achieved. Compared to the IF and AF treatments, the UIF treated PGP samples possessed better microstructure. Therefore, UIF could induce the formation of ice crystals with smaller size and more even distribution during freezing process, which contributed to less damage to the muscle tissue and more satisfied product quality.


Assuntos
Carne de Porco , Animais , Culinária , Congelamento , Suínos , Água
10.
Comput Methods Programs Biomed ; 200: 105943, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33515846

RESUMO

BACKGROUND AND OBJECTIVE: The purpose of this study was to develop a quantitative structure-activity relationship (QSAR) model for the prediction of blood brain barrier (BBB) permeability by using artificial neural networks (ANN) in combination with molecular structure and property descriptors. METHODS: Using a database composed of 300 compounds, 52 structure descriptors obtained based on the universal quasichemical functional group activity coefficients (UNIFAC) group contribution method and the selected 8 molecular property descriptors were used as the network inputs, whereas logBB values of compounds constituted its output. RESULTS: The correlation coefficient R of the constructed prediction model, the relative error (RE) and the root mean square error (RMSE) was 0.956, 0.857, and 0.171, respectively. These indicators reflected the feasibility, robustness and accuracy of the prediction model. Compared with the previously published results, a significant improvement in the predictions of the proposed ANN model was observed. CONCLUSIONS: ANN model based on the group contribution method could achieve a satisfactory performance for logBB prediction.


Assuntos
Barreira Hematoencefálica , Redes Neurais de Computação , Bases de Dados Factuais , Permeabilidade , Relação Quantitativa Estrutura-Atividade
11.
J Mol Model ; 26(8): 198, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632503

RESUMO

In this study, the preparation of molecularly imprinted polymers for bilobalide (BBMIPs) was successfully achieved by bulk polymerization with methacrylamide (MAM), trimethylolpropane triacrylate (TMPTA), and acetonitrile (ACN) as functional monomer, cross-linker, and solvent, respectively. After Gaussian software simulation and single factor experiments, the prepared MIPs with a molar ratio of 1:4:15 for BB-MAM-TMPTA were systematically characterized. The hydrogen bonding interaction between BB and MAM was confirmed by a combination of FTIR and NMR analysis. Thermal gravimetric analysis results displayed that MIPs have excellent thermal stability under high temperature. Additionally, the average pore size and surface area of MIPs were found to be higher than those of NIPs through nitrogen adsorption results. The results of static adsorption and kinetic adsorption suggested that the adsorption equilibrium concentration was 0.6 mg/mL and the equilibrium time was 5 h, and the Langmuir and pseudo-second-order kinetic models were proven to fit with static and kinetic adsorption behaviors, respectively. Meanwhile, the selective adsorption study revealed that MIPs show high adsorption and great selectivity towards BB in comparison with other substances having similarly structure. MIPs also possessed a good performance on reusability, maintaining a high recovery rate after being reused 5 times. The application experiment further indicated that MIPs can effectively separate BB from low purity samples. Therefore, the prepared MIPs had a great potential for BB separation.

12.
Mol Cancer ; 19(1): 42, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32106863

RESUMO

BACKGROUND: The CDKN2A/B locus contains crucial tumor suppressors and a lncRNA gene ANRIL. However, the mechanisms that coordinately regulate their expression levels are not clear. METHODS: Novel RNAs transcribed from the CDKN2A gene were screened by CDKN2A-specific RNA capture deep-sequencing and confirmed by Northern blotting and clone-sequencing. Long non-coding RNA (lncRNA) binding proteins were characterized by RNA pull-down combined with mass spectrometry and RNA immunoprecipitation. LncRNA functions in human cells were studied using a set of biological assays in vitro and in vivo. RESULTS: We characterized a novel lncRNA, P14AS with its promoter in the antisense strand of the fragment near CDKN2A exon 1b in human cells. The mature P14AS is a three-exon linear cytoplasmic lncRNA (1043-nt), including an AU-rich element (ARE) in exon 1. P14AS decreases AUF1-ANRIL/P16 RNA interaction and then increases ANRIL/P16 expression by competitively binding to AUF1 P37 and P40 isoforms. Interestingly, P14AS significantly promoted the proliferation of cancer cells and tumor formation in NOD-SCID mice in a P16-independent pattern. Moreover, in human colon cancer tissues, the expression levels of P14AS and ANRIL lncRNAs were significantly upregulated compared with the paired normal tissues. CONCLUSION: A novel lncRNA, P14AS, transcribed from the antisense strand of the CDKN2A/P14 gene, promotes colon cancer development by cis upregulating the expression of oncogenic ANRIL.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteína Nuclear Heterogênea D0/metabolismo , RNA Longo não Codificante/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Feminino , Ribonucleoproteína Nuclear Heterogênea D0/genética , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
World J Gastroenterol ; 26(2): 184-198, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31988584

RESUMO

BACKGROUND: The expression of the membrane receptor protein GFRA1 is frequently upregulated in many cancers, which can promote cancer development by activating the classic RET-RAS-ERK and RET-RAS-PI3K-AKT pathways. Several therapeutic anti-GFRA1 antibody-drug conjugates are under development. Demethylation (or hypomethylation) of GFRA1 CpG islands (dmGFRA1) is associated with increased gene expression and metastasis risk of gastric cancer. However, it is unknown whether dmGFRA1 affects the metastasis of other cancers, including colon cancer (CC). AIM: To study whether dmGFRA1 is a driver for CC metastasis and GFRA1 is a potential therapeutic target. METHODS: CC and paired surgical margin tissue samples from 144 inpatients and normal colon mucosal biopsies from 21 noncancer patients were included in this study. The methylation status of GFRA1 islands was determined by MethyLight and denaturing high-performance liquid chromatography and bisulfite-sequencing. Kaplan-Meier analysis was used to explore the effect of dmGFRA1 on the survival of CC patients. Impacts of GFRA1 on CC cell proliferation and migration were evaluated by a battery of biological assays in vitro and in vivo. The phosphorylation of AKT and ERK proteins was examined by Western blot analysis. RESULTS: The proportion of dmGFRA1 in CC, surgical margin, and normal colon tissues by MethyLight was 68.4%, 73.4%, and 35.9% (median; nonparametric test, P = 0.001 and < 0.001), respectively. Using the median value of dmGFRA1 peak area proportion as the cutoff, the proportion of dmGFRA1-high samples was much higher in poorly differentiated CC samples than in moderately or well-differentiated samples (92.3%% vs 55.8%, Chi-square test, P = 0.002) and significantly higher in CC samples with distant metastasis than in samples without (77.8% vs 46.0%, P = 0.021). The overall survival of patients with dmGFRA1-low CC was significantly longer than that of patients with dmGFRA1-high CC (adjusted hazard ratio = 0.49, 95% confidence interval: 0.24-0.98), especially for 89 CC patients with metastatic CC (adjusted hazard ratio = 0.41, 95% confidence interval: 0.18-0.91). These data were confirmed by the mining results from TCGA datasets. Furthermore, GFRA1 overexpression significantly promoted the proliferation/invasion of RKO and HCT116 cells and the growth of RKO cells in nude mice but did not affect their migration. GFRA1 overexpression markedly increased the phosphorylation levels of AKT and ERK proteins, two key molecules in two classic GFRA1 downstream pathways. CONCLUSION: GFRA1 expression is frequently reactivated by DNA demethylation in CC tissues and is significantly associated with a poor prognosis in patients with CC, especially those with metastatic CC. GFRA1 can promote the proliferation/growth of CC cells, probably by the activation of AKT and ERK pathways. GFRA1 might be a therapeutic target for CC patients, especially those with metastatic potential.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Animais , Biópsia , Proliferação de Células/genética , Colo/patologia , Colo/cirurgia , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Ilhas de CpG/genética , Desmetilação do DNA , Conjuntos de Dados como Assunto , Feminino , Células HCT116 , Humanos , Mucosa Intestinal/patologia , Mucosa Intestinal/cirurgia , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Cancer ; 10(21): 5153-5161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31602268

RESUMO

To investigate whether CD155 is an attractive target for T cell-mediated immunotherapy against human bladder cancer, we examined the novel bispecific antibody anti-CD3 x anti-CD155 (CD155Bi-Ab) for its ability to redirect activated T cells (ATCs) to target bladder cancer cells was examined. Expression of CD155 was detected by flow cytometry on the surface of bladder cancer cells, including T24 and Pumc-91 cells, and their chemotherapeutic drug-resistant counterparts. ATCs generated from healthy donors were stimulated with anti-CD3 monoclonal antibody, anti-CD28 monoclonal antibody and interleukin-2 (IL-2) for 14 days. The cytotoxic activity of ATCs armed with CD155Bi-Ab against bladder cancer cells was detected by LDH and luciferase quantitative assay. Furthermore, ATCs generated from bladder cancer patients were also armed with CD155Bi-Ab to verity the cell killing by the same methods. In contrast to unarmed ATCs, CD155Bi-armed ATCs against bladder cancer cells were increased cytotoxic activity at effector/target (E/T) ratios of 5:1, 10:1, and 20:1, with more IFN-γ, TNF-α secreting. It is worth noting that in spite of the presence of immunosuppression in bladder cancer patients and the drug resistance in chemotherapeutic drug-resistant cancer cell lines, not only the anti-tumor effect of CD155Bi-armed ATCs generated from bladder cancer patients still showed significantly but only higher level of activation marker CD69 was expressed. Taken together, our results suggest that CD155 is an effective target for the CD155-positive bladder cancer. And CD155Bi-Ab-armed ATCs are promisingly to provide a novel strategy for current CD155-positive bladder cancer therapy.

15.
Invest New Drugs ; 37(5): 810-817, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30374653

RESUMO

Expression of CD155 differs between tumor and normal tissues, and high expression of this molecule can promote tumor metastasis. Here, we investigate whether CD155 can serve as a target for T cell-mediated immunotherapy of human prostate cancer. We first demonstrate that prostate cancer cells, including PC-3, PC-3 M, and LNCAP cells, express CD155 at high levels. Next, the specific cytotoxic activity of activated T cells (ATCs) armed with a novel anti-CD3 × anti-CD155 bispecific antibody (CD155Bi-Ab) against tumor cells was evaluated by flow cytometry, lactate dehydrogenase assay (LDH), and ELISA. In contrast to unarmed ATCs, an increase in the cytotoxic activity of CD155Bi-armed ATCs against tumor cells was observed at an effector/target (E/T) ratio of 5:1. Moreover, CD155Bi-armed ATCs secreted more IFN-γ, TNF-α, and IL-2 and expressed higher levels of the activation marker CD69 than did unarmed ATCs. As CD155 Bi-Ab enhances the ability of ATCs to kill prostate cancer cells, CD155 is an effective target for cytotoxic T cells in human prostate cancer therapy.


Assuntos
Anticorpos Biespecíficos/farmacologia , Antineoplásicos/farmacologia , Complexo CD3/antagonistas & inibidores , Imunoterapia , Neoplasias da Próstata/terapia , Receptores Virais/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Linfócitos T/imunologia , Apoptose , Complexo CD3/imunologia , Proliferação de Células , Humanos , Ativação Linfocitária , Masculino , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Receptores Virais/imunologia , Células Tumorais Cultivadas
16.
Cancer Med ; 7(10): 5167-5177, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30253078

RESUMO

OBJECTIVE: B7-H3 is attractive for cancer immunotherapy with B7-H3 overexpressed tumors. To explore whether B7-H3 is an effective target for patients with bladder cancer, anti-CD3× anti-B7-H3 bispecific antibodies (B7-H3Bi-Ab) was armed with activated T cells (ATC) to kill bladder cancer cells. METHODS: High expressions of B7-H3 on human bladder cancer cells were detected, including Pumc-91 and T24 cells, and their chemotherapeutic drug-resistant counterparts. ATC generated from healthy donors were stimulated with anti-CD3 monoclonal antibody and interleukin-2 (IL-2) for 13 days. The ability of ATC armed with B7-H3Bi-Ab to kill bladder cancer cells was detected by flow cytometry, LDH, Elisa, and luciferase quantitative assay. Moreover, ATC generated from bladder cancer patients was armed with B7-H3Bi-Ab to verity the cell killing by the methods as previously described. RESULTS: Compared with unarmed ATC, a significant increased cytotoxicity of B7-H3Bi-Ab-armed ATC against bladder cancer cells was discovered. The B7-H3Bi-Ab-armed ATC secreted more IFN-γ, TNF-α, and expressed high levels of activation marker CD69. Interestingly, despite the presence of immunosuppression in patients and resistance in chemotherapeutic drug-resistant cancer cell lines, B7-H3Bi-Ab-armed ATC from patients with bladder cancer still showed significant cytotoxic activity against bladder cancer cells and their chemotherapeutic drug-resistant counterparts. CONCLUSION: B7-H3 is an effective target for bladder cancer. B7-H3Bi-Ab enhances the ability of ATC to kill bladder cancer cells. B7-H3Bi-Ab-armed ATC is promisingly to provide a novel strategy for current bladder cancer therapy.


Assuntos
Anticorpos Biespecíficos/metabolismo , Antígenos B7/metabolismo , Complexo CD3/metabolismo , Linfócitos T Citotóxicos/citologia , Neoplasias da Bexiga Urinária/imunologia , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose , Antígenos B7/antagonistas & inibidores , Complexo CD3/antagonistas & inibidores , Linhagem Celular Tumoral , Células Cultivadas , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunoterapia , Interferon gama/metabolismo , Lectinas Tipo C/metabolismo , Ativação Linfocitária , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/transplante , Fator de Necrose Tumoral alfa/metabolismo , Neoplasias da Bexiga Urinária/terapia
17.
Chin J Cancer Res ; 30(1): 93-103, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29545723

RESUMO

OBJECTIVE: To investigate the relationship between the transcription of ANRIL, P15, P14 and P16 at the same locus and the regulation mechanism of ANRIL. METHODS: Publicly available database of Cancer Cell Line Encyclopedia (CCLE) was used in bioinformatic analyses. Methylation of CpG islands was detected by denaturing high performance liquid chromatography (DHPLC). Gene transcript levels were determined using quantitative real-time polymerase chain reaction (qRT-PCR) assays. An engineered P16-specific transcription factor and DNA methyltransferase were used to induce P16-specific DNA demethylation and methylation. RESULTS: The expression level of ANRIL was positively and significantly correlated with that of P16 but not with that of P15 in the CCLE database. This was confirmed in human cell lines and patient colon tissue samples. In addition, ANRIL was significantly upregulated in colon cancer tissues. Transcription of ANRIL and P16 was observed only in cell lines in which the P16 alleles were unmethylated and not in cell lines with fully methylated P16 alleles. Notably, P16-specific methylation significantly decreased transcription of P16 and ANRIL in BGC823 and GES1 cells. In contrast, P16-specific demethylation re-activated transcription of ANRIL and P16 in H1299 cells (P<0.001). Alteration ofANRIL expression was not induced by P16 expression changes. CONCLUSIONS: ANRIL and P16 are coordinately transcribed in human cells and regulated by the methylation status of the P16 CpG islands around the transcription start site.

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