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1.
Sci Rep ; 14(1): 11836, 2024 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-38782965

RESUMEN

Emerging evidence shows that FAT atypical cadherin 1 (FAT1) mutations occur in lymphoma and are associated with poorer overall survival. Considering that diffuse large B cell lymphoma (DLBCL) is the category of lymphoma with the highest incidence rate, this study aims to explore the role of FAT1 in DLBCL. The findings demonstrate that FAT1 inhibits the proliferation of DLBCL cell lines by downregulating the expression of YAP1 rather than by altering its cellular localization. Mechanistic analysis via meRIP-qPCR/luciferase reporter assays showed that FAT1 increases the m6A modification of YAP1 mRNA 3'UTR and the subsequent binding of heterogeneous nuclear ribonucleoprotein D (HNRNPD) to the m6A modified YAP1 mRNA, thus decreasing the stability of YAP1 mRNA. Furthermore, FAT1 increases YAP1 mRNA 3'UTR m6A modification by decreasing the activity of the TGFß-Smad2/3 pathway and the subsequent expression of ALKBH5, which is regulated at the transcriptional level by Smad2/3. Collectively, these results reveal that FAT1 inhibits the proliferation of DLBCL cells by increasing the m6A modification of the YAP1 mRNA 3'UTR via the TGFß-Smad2/3-ALKBH5 pathway. The findings of this study therefore indicate that FAT1 exerts anti-tumor effects in DLBCL and may represent a novel target in the treatment of this form of lymphoma.


Asunto(s)
Regiones no Traducidas 3' , Proteínas Adaptadoras Transductoras de Señales , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso , ARN Mensajero , Factores de Transcripción , Proteínas Señalizadoras YAP , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Línea Celular Tumoral , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Cadherinas/metabolismo , Cadherinas/genética , Adenosina/metabolismo , Adenosina/análogos & derivados , Transducción de Señal
2.
Biochim Biophys Acta Gen Subj ; 1868(1): 130519, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37952564

RESUMEN

BACKGROUND: Emerging studies have shown that FAT atypical cadherin 1 (FAT1) and autophagy separately inhibits and promotes acute myeloid leukemia (AML) proliferation. However, it is unknown whether FAT1 were associated with autophagy in regulating AML proliferation. METHODS: AML cell lines, 6-week-old male nude mice and AML patient samples were used in this study. qPCR/Western blot and cell viability/3H-TdR incorporation assays were separately used to detect mRNA/protein levels and cell activity/proliferation. Luciferase reporter assay was used to examine gene promoter activity. Co-IP analysis was used to detect the binding of proteins. RESULTS: In this study, we for the first time demonstrated that FAT1 inhibited AML proliferation by decreasing AML autophagy level. Moreover, FAT1 weakened AML autophagy level via decreasing autophagy related 4B (ATG4B) expression. Mechanistically, we found that FAT1 reduced the phosphorylated and intranuclear SMAD family member 2/3 (smad2/3) protein levels, thus decreasing the activity of ATG4B gene promoter. Furthermore, we found that FAT1 competitively bound to TGF-ßR II which decreased the binding of TGF-ßR II to TGF-ßR I and the subsequent phosphorylation of TGF-ßR I, thus reducing the phosphorylation and intranuclear smad2/3. The experiments in nude mice showed that knockdown of FAT1 promoted AML autophagy and proliferation in vivo. CONCLUSIONS: Collectively, these results revealed that FAT1 downregulates ATG4B expression via inhibiting TGFß-smad2/3 signaling activity, thus decreasing the autophagy level and proliferation activity of AML cells. GENERAL SIGNIFICANCE: Our study suggested that the "FAT1-TGFß-smad2/3-ATG4B-autophagy" pathway may be a novel target for developing new targeted drugs to AML treatment.


Asunto(s)
Leucemia Mieloide Aguda , Factor de Crecimiento Transformador beta , Ratones , Animales , Humanos , Masculino , Ratones Desnudos , Proliferación Celular , Factor de Crecimiento Transformador beta/farmacología , Leucemia Mieloide Aguda/genética , Autofagia , Cadherinas , Proteínas Relacionadas con la Autofagia/genética , Cisteína Endopeptidasas/metabolismo
3.
Medicine (Baltimore) ; 102(24): e34036, 2023 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-37327301

RESUMEN

RATIONALE: Bone marrow failure (BMF) includes inherited and acquired BMFs. Acquired BMF can be secondary to various factors, such as autoimmune dysfunction, benzene, drugs, radiation, viral infection and so on. Fanconi anemia (FA) complementation group L (FANCL) is an E3 ubiquitin ligase that participates in the repair of DNA damage. Homozygous or compound heterozygous mutations of FANCL can lead to the onset of FA, which is one of the most common inherited BMFs. PATIENT CONCERNS AND DIAGNOSES: Here, we report a case of acquired BMF. This patient had a history of benzene exposure for half a year before the onset of the disease, and presented with progressive pancytopenia, especially the reduction of erythrocytes and megakaryocyte, without malformation. Interestingly, this patient and his brother/father had a heterozygous (non-homozygous/compound heterozygous) mutation (Exon9, c.745C > T, p.H249Y) in the FANCL gene. INTERVENTIONS AND OUTCOMES: The patient successfully underwent unrelated and fully compatible umbilical cord blood hematopoietic stem cell transplantation. LESSONS SUBSECTIONS: We report for the first time an acquired BMF case with FANCL gene heterozygous mutation, and the mutation site (Exon9, c.745C > T, p.H249Y) has never been reported. This case suggests that heterozygous mutations in FANCL gene may be associated with increased susceptibility to acquired BMF. Based on current reports and this case, we speculate that heterozygous mutations in the FA complementation gene may exist in a certain proportion of tumor and acquired BMF patients, but have not been detected. We recommend routine screening for FA complementation gene mutations in tumor and acquired BMF patients in clinical practice. If positive results are found, further screening can be conducted on their families.


Asunto(s)
Anemia de Fanconi , Pancitopenia , Humanos , Masculino , Benceno , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Proteína del Grupo de Complementación L de la Anemia de Fanconi/genética , Heterocigoto , Mutación
4.
Int J Oncol ; 58(2): 275, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33491757

RESUMEN

Following the publication of this paper, it was drawn to the authors' attention by an interested reader that a row of the tumour images featured in Fig. 8A of the above paper were strikingly similar to those featured in Fig. 6A of an article appearing in Oncology Reports that had been published by a different research group at a different institution [Zhang L, Liang X and Li Y: Long non­coding RNA MEG3 inhibits cell growth of gliomas by targeting miR­93 and inactivating PI3K/AKT pathway. Oncol Rep 38: 2408­2416, 2017]. The Editor asked the authors for an explanation to account for the appearance of strikingly similar data in their paper independently, although the authors proved to be uncontactable in this regard, and did not respond to various queries. The Editor has therefore taken an executive decision to retract this paper from International Journal of Oncology without the agreement of the authors. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in International Journal of Oncology 51: 316­326, 2017; DOI: 10.3892/ijo.2017.4006].

5.
J Cell Biochem ; 120(5): 8144-8153, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30556337

RESUMEN

Long noncoding RNAs (lncRNA) are emerging as integral functional and regulatory components in the development of different diseases including cancer. Maternally expressed gene 3 (MEG3), is a lncRNA, that has a depressed expression in multiple tumor types, including T-cell lymphoblastic lymphoma (T-LBL). However, the molecular mechanisms that regulate the tumorigenic functions of MEG3 in T-LBL remain largely unknown. In this study, we aimed to discover and identify the function of MEG3 in T-LBL tumorigenesis, epithelial-mesenchymal transition (EMT) and drug resistance, and explore their mechanisms of action. Knockdown MEG3 promoted the proliferation, migration, invasion, and drug resistance of T-LBL cells while overexpression of MEG3 gets the opposite results. The mechanism study showed that decreased MEG3 expression in T-LBL cells could activate PI3K/mTOR signaling pathways, increase the expression of p-glycoprotein and affect the expression of EMT markers for transforming to mesenchymal cells in vitro and in vivo. Together, these results indicate that MEG3 could inhibit the migration, invasion, and drug resistance in T-LBL cells by suppression of the PI3K/mTOR pathway. MEG3 might be a potential target, through which poor prognosis with high recurrence and drug resistance of T-LBL in a clinical setting could be reversed.

6.
Hematology ; 23(10): 740-746, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29962321

RESUMEN

OBJECTIVES: Acute myeloid leukaemia (AML) is a malignant haematological disease that remains difficult to cure. Cytotoxic T cell (CTL) adoptive infusion therapy may be conducive to tumour remission by boosting physical immunity. Furthermore, programmed death receptor-1 (PD-1) blockade immunotherapy has shown tremendous success in many cancer therapies. METHOD: We attempted to combine these two immunotherapy strategies to intervene in AML by generating AML cellspecific cytotoxic T lymphocytes in vitro and in vivo with an AML cell strain expressing specific antigens. RESULTS: First, we observed that peripheral blood mononuclear cells (PBMCs) could be induced to generate large numbers of CD8+ CTL cells through immune stimulation. In addition, these CD8+ cells could effectively recognize a human AML cell line and exert cytotoxicity. In animal tests, PD-1 blockade combined with CTL infusion could induce significantly more AML tumour reduction than either treatment alone. This synergistic effect was thought to be connected to immune modulation enhancement, as regulatory T cells (Tregs) in the peripheral blood (PB) were found to be suppressed. CONCLUSIONS: This finding suggested the potential application of PD-1 blockade in AML. The present work demonstrated an excellent synergistic tumour therapeutic effect of PD-1 blockade and CTL therapy compared with either treatment alone.


Asunto(s)
Traslado Adoptivo , Linfocitos T CD8-positivos , Leucemia Mieloide Aguda , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/trasplante , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Receptor de Muerte Celular Programada 1/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Int J Oncol ; 51(1): 316-326, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28534937

RESUMEN

T-cell lymphoblastic lymphoma (T-LBL) is an aggressive malignancy with poor prognosis and high recurrence rate. Long non-coding RNA (lncRNA)-MEG3 is an important tumor suppressor in various cancers. The present study investigated the potential role of maternally expressed gene 3 (MEG3) in the progression of T-LBL. Suppressed expression of MEG3 was detected in T-LBL tissues compared with adjacent histologically normal tissues. Down-regulated level of MEG3 was also found in three T-LBL cell lines (CCRF-CEM, Jurkat and SUP-T1) compared with human T-cell line H9. The proliferation of T-LBL cells was inhibited and cell apoptosis rate was largely promoted when MEG3 was upregulated by a lentiviral vector. Further research revealed that microRNA (miRNA)-214 is a direct target of MEG3. The expression of miR-214 was increased in T-LBL tissues and cell lines compared with control groups. Besides, decreased level of miR-214 was elevated adding miR-214 mimic in SUP-T1 cells transfected with LncRNA-MEG3. Similarly, upregulated level of miR-214 was downregulated adding miR-214 inhibitor in SUP-T1 cells transfected with MEG3 siRNA. Luciferase activity assay further confirmed the targeting relationship between MEG3 and miR-214. Moreover, AIFM2 protein was predicted as a target of miR-214. The expression of AIFM2 was increased by MEG3 and was downregulated by miR-214 mimic. miRNA-214 reversed the effect of MEG3 on inhibiting cell proliferation and inducing cell apoptosis and cell cycle arrest in SUP-T1 cells. Moreover, relative expression of AIFM2 had a positive correlation with the expression of MEG3 and was negatively affected by miR-214. In vivo, MEG3 effectively suppressed tumor growth and the expression of proliferation markers Ki-67 and proliferating cell nuclear antigen (PCNA). Taken together, our research revealed that MEG3 worked as an anti-oncogene in T-LBL, and the MEG3-miR-214-AIFM2 pathway regulated the growth of T-LBL, providing potential prognosis markers as well as new potential targets for T-LBL treatment.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Glioma/patología , MicroARNs/genética , Proteínas Mitocondriales/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , ARN Largo no Codificante/genética , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis/genética , Biomarcadores de Tumor/genética , Proliferación Celular , Femenino , Estudios de Seguimiento , Glioma/genética , Glioma/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Proteínas Mitocondriales/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Pronóstico , ARN Largo no Codificante/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Mol Clin Oncol ; 3(6): 1233-1238, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26807226

RESUMEN

Epstein-Barr virus (EBV)-related non-Hodgkin's lymphoma (NHL) represents a major problem in hematological clinical studies due to its drug tolerance and refractoriness. EBV infection is a key factor driving the process of tumor growth. Immune therapy is an important biotherapeutic method of treating cancer, which is attracting increasing attention. We hypothesized that combining conventional chemotherapy with immune therapy in the treatment of EBV-related NHL may achieve better outcomes. First, we successfully cloned large numbers of EBV-specific T cells by immune stimulation ex vivo. Subsequently, the combined therapy was applied in a murine model of human EBV-related NHL. As expected, combined therapy inhibited tumor growth more effectively compared with monotherapy. In addition, we continuously tested the tumor-associated immune microenvironment and observed that the numbers of tumor-infiltrating cytotoxic T lymphocytes (CTLs) and macrophages were elevated following combined therapy. These effects suggest that EBV-specific CTLs may indirectly promote an innate immune reaction in lymphoma by activating tumor-infiltrating macrophage proliferation. Our findings may provide a guide for the prospective treatment of EBV-related NHL.

9.
Zhonghua Xue Ye Xue Za Zhi ; 33(12): 1000-3, 2012 Dec.
Artículo en Chino | MEDLINE | ID: mdl-23363790

RESUMEN

OBJECTIVE: This research was aimed to evaluate the immune mechanism and clinical effect of immunotherapy of dendritic cells (DC) and cytokine-induced killer cell (CIK) combined with chemotherapy on multiple myeloma (MM). METHODS: 60 patients with MM were randomly divided into two groups. 30 patients in chemotherapy group were treated by chemotherapy only, 30 patients in joint group were treated by adoptive immunotherapy (DC-CIK) combined with chemotherapy. A variety of immunological indexes (Hsp70, Th1/Th2, TGF-ß) of all patients before and after chemotherapy were recorded; Also the clinical outcomes between two groups were compared. RESULTS: After chemotherapy, the immunological indexes of all patients were better than those of before chemotherapy (P < 0.05); After treatment, quality of life, clinical index and survival in joint group were better than in chemotherapy group (P < 0.05). CONCLUSION: Chemotherapy could break the immunosuppression of MM and improve the anti-tumor response of DC-CIK; Chemotherapy and DC-CIK may have synergistic effect for MM.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Células Asesinas Inducidas por Citocinas/inmunología , Células Dendríticas/inmunología , Inmunoterapia Adoptiva , Mieloma Múltiple/terapia , Adulto , Anciano , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/inmunología , Resultado del Tratamiento
10.
Stem Cells Dev ; 21(9): 1429-40, 2012 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-22023173

RESUMEN

Stromal cells and mesenchymal stem cells (MSCs), 2 important cell populations within the hematopoietic microenvironment, may play an important role in the development of hematopoietic stem/progenitor cells. We have successfully cultured human umbilical cord blood-derived stromal cells (hUCBDSCs). It has been demonstrated that MSCs also exist in hUCB. However, we have not found any reports on the distinct characteristics of hUCBDSCs and human umbilical cord blood-derived mesenchymal stem cells (hUCBDMSCs). In this study, hUCBDSCs and hUCBDMSCs were isolated from the cord blood of full-term infants using the same density gradient centrifugation and cultured in the appropriate medium. Some biological characteristics and hematopoietic supportive functions were compared in vitro. hUCBDSCs were distinct from hUCBDMSCs in morphology, proliferation, cell cycle, passage, immunophenotype, and the capacity for classical tri-lineage differentiation. Finally, quantitative real-time polymerase chain reaction analysis revealed that granulocyte colony-stimulating factor (G-CSF) gene expression was higher in hUCBDSCs than that in hUCBDMSCs. Enzyme-linked immunosorbent assay revealed that the secretion of G-CSF, thrombopoietin (TPO), and granulocyte macrophage colony-stimulating factor (GM-CSF) by hUCBDSCs was higher than that by hUCBDMSCs. After coculture, the granulocyte/macrophage colony-forming units (CFU-GM) of hematopoietic cells from the hUCBDSC feeder layer was more than that from the hUCBDMSC feeder layer. Flow cytometry was used to detect CD34(+) hematopoietic stem/progenitor cell committed differentiation during 14 days of coculture; the results demonstrated that CD14 and CD33 expression in hUCBDSCs was significantly higher than their expression in hUCBDMSCs. This observation was also true for the granulocyte lineage marker, CD15. This marker was expressed beginning at day 7 in hUCBDSCs. It was expressed earlier and at a higher level in hUCBDSCs compared with hUCBDMSCs. In conclusion, hUCBDSCs are different from hUCBDMSCs. hUCBDSCs are superior to hUCBDMSCs in supporting hematopoiesis stem/progenitor cells differentiation into myeloid lineage cells at an early stage in vitro.


Asunto(s)
Diferenciación Celular/fisiología , Células Progenitoras de Granulocitos y Macrófagos/citología , Células Progenitoras de Granulocitos y Macrófagos/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Antígenos CD/biosíntesis , Ciclo Celular/fisiología , Células Cultivadas , Técnicas de Cocultivo , Citocinas/biosíntesis , Sangre Fetal , Regulación de la Expresión Génica/fisiología , Humanos , Células del Estroma/citología , Células del Estroma/metabolismo , Factores de Tiempo
11.
Hepatobiliary Pancreat Dis Int ; 7(1): 51-7, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18234639

RESUMEN

BACKGROUND: The pathogenesis of hepatic fibrosis and cirrhosis is still not fully understood. The extracellular signal-regulated kinase (ERK) pathway is involved in the regulation of cell proliferation and differentiation. The aim of this study was to investigate the effects of PD98059, a specific inhibitor of ERK, on the cell cycle, cell proliferation, secretion of type I collagen and expression of cyclin D1 mRNA, CDK4 mRNA and transforming growth factor-beta1 (TGF-beta1) mRNA in rat hepatic stellate cells (HSCs) stimulated by acetaldehyde. METHODS: Rat HSCs stimulated by acetaldehyde were incubated with PD98059 at different concentrations. The cell cycle was analysed by flow cytometry. Cell proliferation was assessed by the methyl thiazolyl tetrazolium colorimetric assay. The mRNA expression of cyclin D1, CDK4 and TGF-beta1 was examined using the reverse transcriptase-polymerase chain reaction. Type I collagen in the culture medium was detected by enzyme-linked immunosorbent assay. RESULTS: 20, 50 and 100 micromol/L PD98059 significantly inhibited the proliferation and provoked a G0/G1-phase arrest of acetaldehyde-induced HSCs in a dose-dependent manner. The secretion of type I collagen and the expression of cyclin D1, CDK4 and TGF-beta1 mRNA in acetaldehyde-induced HSCs were markedly inhibited by 50 and 100 micromol/L PD98059, respectively. CONCLUSIONS: The ERK pathway regulates the cell proliferation, secretion of type I collagen and the expression of TGF-beta1 mRNA in rat HSCs stimulated by acetaldehyde, which is likely related to its regulative effect on the cell cycle.


Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hepatocitos/enzimología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Sistema de Señalización de MAP Quinasas/fisiología , Acetaldehído/farmacología , Animales , Células Cultivadas , Colágeno Tipo I/metabolismo , Ciclina D1/genética , Quinasa 4 Dependiente de la Ciclina/genética , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Fase G1/efectos de los fármacos , Fase G1/fisiología , Hepatocitos/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas , Fase de Descanso del Ciclo Celular/efectos de los fármacos , Fase de Descanso del Ciclo Celular/fisiología , Factor de Crecimiento Transformador beta1/genética
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