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1.
Cancer Sci ; 112(1): 144-154, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33113266

ABSTRACT

Eomesodermin (Eomes) is a T-box transcription factor that drives the differentiation and function of cytotoxic lymphocytes. However, the underlying function and mechanism of Eomes in tumor cells remains elusive. Here, we studied the role of Eomes in human esophageal squamous cell carcinoma (ESCC). Using 2 human ESCC cell lines, we found that Eomes knockdown reduced esophageal cancer cell proliferation and that the esophageal cancer cell cycle was blocked in the G2/M phase. Mechanistically, we identified CCL20 as the main downstream target of Eomes. Furthermore, we found that CCL20 could chemoregulate regulatory T cells (Tregs) through their specific receptor CCR6, then promoting the proliferation of esophageal cancer cells. Eomes knockdown also delayed the growth of human ESCC xenografts in BALB/c nude mice. Importantly, in 133 human ESCC tissues, high Eomes levels were associated with poor clinical prognosis. Overall, our findings suggested that the Eomes-CCL20-CCR6 pathway plays a vital role in human ESCC progress. Therefore, targeting this pathway may represent a promising strategy for controlling human ESCC.


Subject(s)
Chemokine CCL20/immunology , Esophageal Neoplasms/immunology , Esophageal Squamous Cell Carcinoma/immunology , Receptors, CCR6/immunology , T-Box Domain Proteins/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Cell Line, Tumor , Cell Movement/immunology , Cell Proliferation/physiology , Disease Progression , Female , G2 Phase Cell Cycle Checkpoints/immunology , Gene Expression Regulation, Neoplastic/immunology , Heterografts/immunology , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Prognosis
2.
Sci Rep ; 8(1): 11627, 2018 08 02.
Article in English | MEDLINE | ID: mdl-30072701

ABSTRACT

There is no safe and efficacious vaccine against human leishmaniasis available and live attenuated vaccines have been used as a prophylactic alternative against the disease. In order to obtain an attenuated Leishmania parasite for vaccine purposes, we generated L. infantum KHARON1 (KH1) null mutants (ΔLikh1). This gene was previously associated with growth defects in L. mexicana. ΔLikh1 was obtained and confirmed by PCR, qPCR and Southern blot. We also generate a KH1 complemented line with the introduction of episomal copies of KH1. Although ΔLikh1 promastigote forms exhibited a growth pattern similar to the wild-type line, they differ in morphology without affecting parasite viability. L. infantum KH1-deficient amastigotes were unable to sustain experimental infection in macrophages, forming multinucleate cells which was confirmed by in vivo attenuation phenotype. The cell cycle analysis of ΔLikh1 amastigotes showed arrested cells at G2/M phase. ΔLikh1-immunized mice presented reduced parasite burden upon challenging with virulent L. infantum, when compared to naïve mice. An effect associated with increased Li SLA-specific IgG serum levels and IL-17 production. Thus, ΔLikh1 parasites present an infective-attenuated phenotype due to a cytokinesis defect, whereas it induces immunity against visceral leishmaniasis in mouse model, being a candidate for antileishmanial vaccine purposes.


Subject(s)
Cytokinesis , Leishmania infantum , Leishmaniasis, Visceral , Mutation , Animals , Cytokinesis/genetics , Cytokinesis/immunology , Disease Models, Animal , G2 Phase Cell Cycle Checkpoints/genetics , G2 Phase Cell Cycle Checkpoints/immunology , Humans , Leishmania infantum/genetics , Leishmania infantum/growth & development , Leishmania infantum/immunology , Leishmaniasis, Visceral/genetics , Leishmaniasis, Visceral/immunology , Leishmaniasis, Visceral/metabolism , Leishmaniasis, Visceral/prevention & control , M Phase Cell Cycle Checkpoints/genetics , M Phase Cell Cycle Checkpoints/immunology , Macrophages/immunology , Macrophages/metabolism , Macrophages/parasitology , Mice , Mice, Inbred BALB C , Mice, Knockout , Plasmids/genetics , Plasmids/immunology , Plasmids/metabolism , THP-1 Cells
3.
Sultan Qaboos Univ Med J ; 18(4): e440-e446, 2018 Nov.
Article in English | MEDLINE | ID: mdl-30988961

ABSTRACT

OBJECTIVES: Ataxia-telangiectasia (A-T) is an autosomal recessive multisystem disorder characterised by cerebellar degeneration, telangiectasia, radiation sensitivity, immunodeficiency, oxidative stress and cancer susceptibility. Epidemiological research has shown that carriers of the heterozygous ataxia-telangiectasia mutated (ATM) gene mutation are radiosensitive to ionising irradiation and have a higher risk of cancers, type 2 diabetes and atherosclerosis. However, there is currently no fast and reliable laboratory-based method to detect heterozygous ATM carriers for family screening and planning purposes. This study therefore aimed to evaluate the ability of a modified G2-assay to identify heterozygous ATM carriers in the families of A-T patients. METHODS: This study took place at the Tehran University of Medical Sciences, Tehran, Iran, between February and December 2017 and included 16 A-T patients, their parents (obligate heterozygotes) and 30 healthy controls. All of the subjects underwent individual radiosensitivity (IRS) assessment using a modified caffeine-treated G2-assay with G2-checkpoint abrogation. RESULTS: The mean IRS of the obligate ATM heterozygotes was significantly higher than the healthy controls (55.13% ± 5.84% versus 39.03% ± 6.95%; P <0.001), but significantly lower than the A-T patients (55.13% ± 5.84% versus 87.39% ± 8.29%; P = 0.001). A receiver operating characteristic (ROC) curve analysis of the G2-assay values indicated high sensitivity and specificity, with an area under the ROC curve of 0.97 (95% confidence interval: 0.95-1.00). CONCLUSION: The modified G2-assay demonstrated adequate precision and relatively high sensitivity and specificity in detecting heterozygous ATM carriers.


Subject(s)
Ataxia Telangiectasia/radiotherapy , Radiation Tolerance/immunology , Adolescent , Adult , Ataxia Telangiectasia/epidemiology , Ataxia Telangiectasia Mutated Proteins/therapeutic use , Atherosclerosis/epidemiology , Caffeine/therapeutic use , Child , Child, Preschool , Diabetes Mellitus, Type 2/epidemiology , Female , G2 Phase Cell Cycle Checkpoints/immunology , Humans , Iran , Male , Middle Aged , Neoplasms/epidemiology
4.
Biochem J ; 474(24): 4207-4218, 2017 Dec 14.
Article in English | MEDLINE | ID: mdl-29150436

ABSTRACT

Studies have demonstrated that microvesicles (MVs) derived from human Wharton's Jelly mesenchymal stromal cells (hWJMSCs) could ameliorate renal ischemia/reperfusion injury (IRI); however, the underlying mechanisms were not clear yet. Here, MVs were isolated and injected intravenously into rats immediately after ischemia of the left kidney, and Erk1/2 activator hepatocyte growth factor (HGF) or inhibitor U0126 was administrated. Tubular cell proliferation and apoptosis were identified by Ki67 or terminal-deoxynucleotidyl transferase-mediated nick end labeling immunostaining. Masson's tri-chrome straining and alpha-smooth muscle actin staining were used for assessing renal fibrosis. The mRNA or protein expression in the kidney was measured by quantitative reverse transcription-PCR or Western blot, respectively. The total collagen concentration was also determined. In vitro, NRK-52E cells that treated with MVs under hypoxia injury and with HGF or U0126 administration were used, and cell cycle analysis was performed. The effects of hWJMSC-MVs on enhancing the proliferation and mitigating the apoptosis of renal cells, abrogating IRI-induced fibrosis, improving renal function, decreasing collagen deposition, and altering the expression levels of epithelial-mesenchymal transition and cell cycle-related proteins in IRI rats were found. In vitro experiment showed that hWJMSC-MVs could induce G2/M cell cycle arrest and decrease the expression of collagen deposition-related proteins in NRK-52E cells after 24 or 48 h. However, U0126 treatment reversed these effects. In conclusion, MVs derived from hWJMSCs ameliorate IR-induced renal fibrosis by inducing G2/M cell cycle arrest via Erk1/2 signaling.


Subject(s)
Cell-Derived Microparticles/immunology , G2 Phase Cell Cycle Checkpoints/immunology , Kidney/immunology , Reperfusion Injury/immunology , Animals , Apoptosis/drug effects , Apoptosis/immunology , Butadienes/pharmacology , Cell Line , Cell-Derived Microparticles/metabolism , Enzyme Inhibitors/pharmacology , Fibrosis/immunology , Fibrosis/metabolism , Fibrosis/prevention & control , G2 Phase Cell Cycle Checkpoints/drug effects , Hepatocyte Growth Factor/pharmacology , Humans , Kidney/metabolism , Kidney/pathology , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/immunology , Mesenchymal Stem Cells/metabolism , Nitriles/pharmacology , Rats , Wharton Jelly/metabolism
5.
J Neurovirol ; 22(4): 403-15, 2016 08.
Article in English | MEDLINE | ID: mdl-27056720

ABSTRACT

It is increasingly evident that the human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) has a unique role in neuropathogenesis. Its ability to induce G2/M arrest coupled with its capacity to increase viral gene transcription gives it a unique role in sustaining viral replication and aiding in the establishment and maintenance of a systemic infection. The requirement of Vpr for HIV-1 infection and replication in cells of monocytic origin (a key lineage of cells involved in HIV-1 neuroinvasion) suggests an important role in establishing and sustaining infection in the central nervous system (CNS). Contributions of Vpr to neuropathogenesis can be expanded further through (i) naturally occurring HIV-1 sequence variation that results in functionally divergent Vpr variants; (ii) the dual activities of Vpr as a intracellular protein delivered and expressed during HIV-1 infection and as an extracellular protein that can act on neighboring, uninfected cells; (iii) cell type-dependent consequences of Vpr expression and exposure, including cell cycle arrest, metabolic dysregulation, and cytotoxicity; and (iv) the effects of Vpr on exosome-based intercellular communication in the CNS. Revealing that the effects of this pleiotropic viral protein is an essential part of a greater understanding of HIV-1-associated pathogenesis and potential approaches to treating and preventing disease caused by HIV-1 infection.


Subject(s)
Central Nervous System/virology , Gene Expression Regulation, Viral , HIV Infections/virology , HIV-1/genetics , Host-Pathogen Interactions/immunology , vpr Gene Products, Human Immunodeficiency Virus/genetics , Bystander Effect/genetics , Bystander Effect/immunology , Central Nervous System/immunology , Central Nervous System/pathology , G2 Phase Cell Cycle Checkpoints/genetics , G2 Phase Cell Cycle Checkpoints/immunology , HIV Infections/genetics , HIV Infections/immunology , HIV Infections/pathology , HIV-1/growth & development , HIV-1/immunology , Humans , Monocytes/immunology , Monocytes/pathology , Monocytes/virology , Neurons/immunology , Neurons/pathology , Neurons/virology , Signal Transduction , T-Lymphocytes/immunology , T-Lymphocytes/pathology , T-Lymphocytes/virology , Virus Replication , vpr Gene Products, Human Immunodeficiency Virus/immunology
6.
Ross Fiziol Zh Im I M Sechenova ; 100(11): 1268-79, 2014 Nov.
Article in Russian | MEDLINE | ID: mdl-25665405

ABSTRACT

It has been shown that psychoneurological disorders are accompanied by different disturbances of immunity. Paper aimed to study the effects of repeated experience of aggression in daily agonistic interactions leading to the development of behavioral psychopathology on the parameters of cellular immunity in the thymus and spleen. There were no found the changes in the weight indexes, the number of cells in the thymus, spleen and blood in aggressive mice. In the spleen of aggressive mice percent of B-lymphocytes--CD19+ and CD16/32+, as well as T-lymphocytes CD4+8-, CD4-8+, and CD4+25(hi) decreased and percent of CD4-25+ increased in comparison with the controls. In the thymus percent of CD4-25+ cells are decreased without changes of other types of lymphocytes. Flow cytometric analysis revealed decreased percentage of apoptotic (A(0)) and resting (G0/G1) cells and increased percentage of proliferating cells in phase S+G2/M in the spleen of aggressive male mice in comparison with the control. The percentage of apoptotic thymocytes is increased and the percentage of thymocytes in S+G2/M phase is decreased under the repeated experience of aggression. Data suggest the possible development of an autoimmune procceses in male mice under the influence of repeated experience of aggression.


Subject(s)
Aggression/psychology , B-Lymphocyte Subsets/immunology , Spleen/immunology , Stress, Psychological/immunology , T-Lymphocyte Subsets/immunology , Thymus Gland/immunology , Animals , Antigens, CD/genetics , Antigens, CD/immunology , Autoimmunity , B-Lymphocyte Subsets/pathology , Cell Proliferation , G1 Phase/genetics , G1 Phase/immunology , G2 Phase Cell Cycle Checkpoints/genetics , G2 Phase Cell Cycle Checkpoints/immunology , Gene Expression , Immunity, Innate , Immunophenotyping , Lymphocyte Count , Male , Mice , Mice, Inbred C57BL , Spleen/pathology , Stress, Psychological/pathology , T-Lymphocyte Subsets/pathology , Thymus Gland/pathology
7.
J Biol Chem ; 288(23): 16334-16347, 2013 Jun 07.
Article in English | MEDLINE | ID: mdl-23625925

ABSTRACT

The multikinase inhibitors sunitinib, sorafenib, and axitinib have an impact not only on tumor growth and angiogenesis, but also on the activity and function of immune effector cells. In this study, a comparative analysis of the growth inhibitory properties and apoptosis induction potentials of tyrosine kinase inhibitors on T cells was performed. Tyrosine kinase inhibitor treatment resulted in a dramatic decrease in T cell proliferation along with distinct impacts on the cell cycle progression. This was at least partially associated with an enhanced induction of apoptosis although triggered by distinct apoptotic mechanisms. In contrast to sunitinib and sorafenib, axitinib did not affect the mitochondrial membrane potential (Δψm) but resulted in an induction or stabilization of the induced myeloid leukemia cell differentiation protein (Mcl-1), leading to an irreversible arrest in the G2/M cell cycle phase and delayed apoptosis. Furthermore, the sorafenib-mediated suppression of immune effector cells, in particular the reduction of the CD8(+) T cell subset along with the down-regulation of key immune cell markers such as chemokine CC motif receptor 7 (CCR7), CD26, CD69, CD25, and CXCR3, was not observed in axitinib-treated immune effector cells. Therefore, axitinib rather than sorafenib seems to be suitable for implementation in complex treatment regimens of cancer patients including immunotherapy.


Subject(s)
CD8-Positive T-Lymphocytes/enzymology , Imidazoles/pharmacology , Immunosuppressive Agents/pharmacology , Indazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Antigens, CD/immunology , Antigens, CD/metabolism , Apoptosis/drug effects , Apoptosis/immunology , Axitinib , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Female , G2 Phase Cell Cycle Checkpoints/drug effects , G2 Phase Cell Cycle Checkpoints/immunology , Humans , Jurkat Cells , M Phase Cell Cycle Checkpoints/drug effects , M Phase Cell Cycle Checkpoints/immunology , Male , Membrane Potential, Mitochondrial/drug effects , Myeloid Cell Leukemia Sequence 1 Protein , Neoplasms/drug therapy , Neoplasms/enzymology , Neoplasms/immunology , Proto-Oncogene Proteins c-bcl-2/immunology , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptors, CCR7/immunology , Receptors, CCR7/metabolism , Receptors, CXCR3/immunology , Receptors, CXCR3/metabolism
8.
J Immunol ; 189(10): 4748-58, 2012 Nov 15.
Article in English | MEDLINE | ID: mdl-23071284

ABSTRACT

The TNF superfamily ligands APRIL and BAFF bind with different affinity to two receptors, BCMA and TACI, and induce cell survival and/or proliferation, whereas BAFF also binds specifically to BAFFR. These molecules were considered specific for the immune system. Recently, however, they were also found in epithelial and mesenchymal noncancerous and cancerous tissues and cell lines. In this article, we report that hepatocellular carcinoma (HCC) cell lines HepG2 and Hep3B and HCC specimens express APRIL and BAFF and their receptors BCMA and BAFFR, but not TACI; APRIL/BCMA is enhanced in HCC, compared with normal liver tissue. In contrast to previous reports, APRIL binding to BCMA decreases cell proliferation by inducing G(2)/M cell cycle arrest, whereas BAFF has no effect on cell growth. HCC cells therefore represent a rare system in which these two ligands (APRIL and BAFF) exert a differential effect and may serve as a model for specific APRIL/BCMA actions. We show that the effect of APRIL is mediated via BCMA, which does not activate the classical NF-κB pathway, whereas it induces a novel signaling pathway, which involves JNK2 phosphorylation, FOXO3A activation, and GADD45 transcription. In addition, JNK2 mediates the phosphorylation of Akt, which is activated but does not participate in the antiproliferative effect of APRIL. Furthermore, transcriptome analysis revealed that APRIL modifies genes specifically related to cell cycle modulation, including MCM2/4/5/6, CDC6, PCNA, and POLE2. Our data, therefore, identify a novel APRIL/BCMA signaling pathway in HCC and suggest that APRIL could have a pleiotropic role in tumor biology.


Subject(s)
B-Cell Maturation Antigen/immunology , Cell Cycle Proteins/immunology , DNA-Binding Proteins/immunology , Forkhead Transcription Factors/immunology , G2 Phase Cell Cycle Checkpoints/immunology , Liver/immunology , M Phase Cell Cycle Checkpoints/immunology , MAP Kinase Kinase 7/immunology , Nuclear Proteins/immunology , Transcription Factors/immunology , B-Cell Activating Factor/genetics , B-Cell Activating Factor/immunology , B-Cell Activating Factor/metabolism , B-Cell Maturation Antigen/genetics , B-Cell Maturation Antigen/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Forkhead Box Protein O3 , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , G2 Phase Cell Cycle Checkpoints/genetics , Hep G2 Cells , Humans , Liver/cytology , M Phase Cell Cycle Checkpoints/genetics , MAP Kinase Kinase 7/genetics , MAP Kinase Kinase 7/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Phosphorylation/genetics , Phosphorylation/immunology , Proliferating Cell Nuclear Antigen/genetics , Proliferating Cell Nuclear Antigen/immunology , Proliferating Cell Nuclear Antigen/metabolism , Protein Binding , Transcription Factors/genetics , Transcription Factors/metabolism , Transcription, Genetic/genetics , Transcription, Genetic/immunology
9.
Cancer Immunol Immunother ; 61(7): 979-89, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22120758

ABSTRACT

Ovarian cancer comprises a small population of cancer stem cells (CSCs) that are responsible for tumor maintenance and resistant to cancer therapies, it would be desirable to develop a therapy that could selectively target ovarian CSCs. Recently, cellular immune-based therapies have improved the prognosis of cancer patients clinically. In this study, we isolated a subset of ovarian cancer sphere cells that possess CSC properties and explored the cell cytotoxicity of γδ T cells to ovarian cancer sphere cells using a transwell cocultured cell system. The proliferation rate of the cancer sphere cells decreased to 40% after cocultured with γδ T cells. The γδ T cells increased the sensitivity of SK-OV-3 sphere cells to chemotherapeutic drugs. After the treatment of γδ T cells, the expression of stem cell marker genes decreased in sphere cells, while the expression of HLA-DR antigen on tumor cells was increased in a time-dependent manner. Further, γδ T cells induced G2/M phase cell cycle arrest and subsequent apoptosis in SK-OV-3 sphere cells. Xenograft mouse models demonstrated that γδ T cells dramatically reduced the tumor burden. Notably, the level of IL-17 production significantly increased after cocultured with γδ T cells. We conclude that γδ T cells may efficiently kill ovarian CSCs through IL-17 production and represent a promising immunotherapy for ovarian cancer.


Subject(s)
Immunotherapy, Adoptive/methods , Neoplasms, Glandular and Epithelial/therapy , Neoplastic Stem Cells/immunology , Ovarian Neoplasms/therapy , Receptors, Antigen, T-Cell, gamma-delta/immunology , T-Lymphocytes/immunology , Animals , Apoptosis/immunology , Carcinoma, Ovarian Epithelial , Cell Line, Tumor , Coculture Techniques , Female , G2 Phase Cell Cycle Checkpoints/immunology , HLA-DR Antigens/biosynthesis , HLA-DR Antigens/immunology , Humans , Interleukin-17/biosynthesis , Interleukin-17/immunology , M Phase Cell Cycle Checkpoints/immunology , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasms, Glandular and Epithelial/drug therapy , Neoplasms, Glandular and Epithelial/immunology , Neoplasms, Glandular and Epithelial/pathology , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Xenograft Model Antitumor Assays
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