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Aberrant expression of DEPDC1B (DEP domain-containing protein 1B) has been shown to be associated with various types of malignant tumors. However, little is known about the role of DEPDC1B in epithelial ovarian cancer (EOC). The purpose of this study was to investigate the expression and role of DEPDC1B in EOC. Immunohistochemical staining of 60 high-grade serous ovarian cancer (HGSOC) showed that DEPDC1B expression was associated with response to first line chemotherapy, and DEPDC1B expression was higher in platinum-resistant patients than in platinum-sensitive patients. However, there was no association between DEPDC1B expression and age, preoperative CA125 level, ascites status, location, FIGO stage, and residual disease. Furthermore, our study demonstrated that increased DEPDC1B expression was correlated with reduced overall survival (OS) and progression-free survival (PFS) time in patients with HGSOC. Multivariate analysis showed that DEPDC1B independently predicted OS in patients with HGSOC. However, DEPDC1B expression was not an independent prognostic factor for PFS in patients with HGSOC. Moreover, our study demonstrated that DEPDC1B could promote the proliferation of OVCAR3 and SKOV3 cells by enhancing AKT phosphorylation at Ser473. Treatment with MK2206 and LY294002 significantly suppressed cell proliferation that is induced by DEPDC1B up-regulation in both OVCAR3 and SKOV3 cells. Together, these results revealed that DEPDC1B was an independent prognostic factor for OS in patients with HGSOC, and DEPDC1B may promote the proliferation of EOC cells via enhancing AKT phosphorylation at Ser473.
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By integrating high molecular rigidity and stable chirality, two pairs of D*-A type circularly polarized thermally activated delayed fluorescence (CP-TADF) emitters with an almost absolute quasi-equatorial conformer geometry and excellent photoluminescence quantum efficiencies (PLQYs) are developed, achieving state-of-the-art electroluminescence performance among blue and orange circularly polarized organic light-emitting diodes (CP-OLEDs).
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The ETFDH (electron transfer flavoprotein dehydrogenase) gene mutations are reported to be a major cause of riboflavin-responsive multiple acyl-coenzyme A dehydrogenation deficiency (MADD). However, the role of ETFDH in the prognosis of hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the expression of ETFDH in HCC. Immunohistochemical staining of the 207 HCC tissue microarray showed that expression of ETFDH was significantly decreased in HCC compared with the matching noncancerous hepatic tissues (P < 0.001). Moreover, ETFDH expression levels were found to be correlated with AFP levels (P = 0.011). Intriguingly, ETFDH expression levels were significantly lower in poorly differentiated or undifferentiated HCCs as compared to the well or moderately differentiated cases (P = 0.001). Kaplan-Meier analysis revealed that low tumor expression of ETFDH was associated with a poorer overall survival in patients with HCC (P = 0.024). Furthermore, multivariate analysis showed that ETFDH (P = 0.047) was an independent predictor of overall survival. Our findings may shed new light on the identification of new prognostic marker for HCC.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/enzimologia , Flavoproteínas Transferidoras de Elétrons/análise , Proteínas Ferro-Enxofre/análise , Neoplasias Hepáticas/enzimologia , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/análise , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Diferenciação Celular , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Análise Serial de Tecidos , alfa-Fetoproteínas/análiseRESUMO
miR-182 is a well-described oncogenic miRNA playing a crucial role in the development of many malignancies. However, the role of miR-182 in multiple myeloma (MM) remains unclear. Here, we demonstrate that adhesion of H929 and MM.1S cells to fibronectin could induce miR-182 expression and decrease PDCD4 expression. Furthermore, miR-182 was found to negatively regulate PDCD4 expression in H929 and MM.1S cells. In addition, PDCD4 down-regulation was required for cell adhesion-mediated drug resistance (CAM-DR). Intriguingly, miR-182 up-regulation could promote CAM-DR in H929 and MM.1S cells. Moreover, miR-182 up-regulation and PDCD4 down-regulation enhanced AKT phosphorylation at Ser473 in both H929 and MM.1S cells. Our data suggest that cell adhesion-mediated miR-182 up-regulation and PDCD4 down-regulation may confer drug resistance via enhancing AKT phosphorylation at Ser473.
Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Mieloma Múltiplo/patologia , Proteínas de Ligação a RNA/biossíntese , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Mieloma Múltiplo/genética , Proteínas Proto-Oncogênicas c-akt/biossínteseRESUMO
PDH E1 component subunit alpha (PDHA1) has been reported to be biologically significant in several human tumors. The aim of this study was to investigate the expression of PDHA1 in gastric cancer (GC) and its relationship with clinicopathological characteristics and prognosis. Oncomine analysis of neoplastic vs. normal tissue showed that the mRNA levels of PDHA1 were significantly underexpressed in different types of GC across three analyses. Underexpression of PDHA1 was found in intestinal-type GC (P = 0.009), diffuse-type GC (P = 0.036), and mixed-type GC (P = 0.025). Immunohistochemical staining of the 174 GC tissue microarray showed that PDHA1 staining is much stronger in normal mucosa than in GC samples (P = 0.040). Furthermore, PDHA1 expression levels were found to be significantly lower in 69.05% (87/126) of poorly differentiated GCs as compared to the well or moderately differentiated ones (P = 0.037). Intriguingly, PDHA1 expression was significantly correlated with depth of invasion (P < 0.001), lymph node metastasis (P < 0.001), TNM stage (P < 0.001), and nerve invasion (P = 0.006). However, it was not correlated with gender, age, Lauren classification, and lymphovascular invasion (P > 0.05 for all). Kaplan-Meier analysis revealed that low tumor expression of PDHA1 was significantly correlated with a poorer overall survival in patients with GC (5-year overall survival rates for patients with low vs high PDHA1 expression = 49.8% vs 72.7%, hazard ratio of death from GC = 2.594, 95% CI = 1.527 to 4.408, P < 0.001). Multivariate analysis showed that PDHA1 (P = 0.025) was an independent predictor of overall survival. These findings are of potential clinical utility and merit further validation.
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Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Piruvato Desidrogenase (Lipoamida)/biossíntese , Neoplasias Gástricas/patologia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/mortalidade , Adulto JovemRESUMO
Dysregulation of TRIM44 has been reported to be involved in tumorigenesis, but its role in hepatocellular carcinoma (HCC) remains unclear. In the present study, we investigated the clinicopathological and biological significance of TRIM44 in HCC. We found that TRIM44 mRNA and protein expression was upregulated in HCC compared with matched normal tissues. Intriguingly, we also found that TRIM44 expression was significantly correlated with tumor size (P < 0.001), vascular invasion (P < 0.001), intrahepatic metastasis (P < 0.001), distant metastasis (P < 0.001), and Ki-67 expression (P < 0.001). Kaplan-Meier analysis showed that high TRIM44 staining was significantly correlated with shorter overall survival (P < 0.001). TRIM44 was an independent predictor of overall survival in patients with HCC. Furthermore, we found that ectopic expression of TRIM44 could promote cell proliferation via accelerating the G1/S-phase transition in HCC. Moreover, overexpression of TRIM44 could enhance the invasive and migratory capacity of HCC cells. Meanwhile, we found that high expression of TRIM44 could enhance resistance of HCC cells to doxorubicin via accelerating NF-κB activation. In conclusion, our results suggest that TRIM44 may be a novel prognostic indicator and potential therapeutic target of HCC.
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Carcinoma Hepatocelular/secundário , Proteínas de Transporte/metabolismo , Movimento Celular , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/patologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Ciclo Celular , Doxorrubicina , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Proteínas com Motivo Tripartido , Células Tumorais CultivadasRESUMO
YB-1 is a multifunctional protein, which has been shown to correlate with resistance to treatment of various tumor types. This study investigated the expression and biologic function of YB-1 in diffuse large B-cell lymphoma (DLBCL). Immunohistochemical analysis showed that the expression statuses of YB-1 and pYB-1(S102) were reversely correlated with the clinical outcomes of DLBCL patients. In addition, we found that YB-1 could promote the proliferation of DLBCL cells by accelerating the G1/S transition. Ectopic expression of YB-1 could markedly increase the expression of cell cycle regulators cyclin D1 and cyclin E. Furthermore, we found that adhesion of DLBCL cells to fibronectin (FN) could increase YB-1 phosphorylation at Ser102 and pYB-1(S102) nuclear translocation. In addition, overexpression of YB-1 could increase the adhesion of DLBCL cells to FN. Intriguingly, we found that YB-1 overexpression could confer drug resistance through cell-adhesion dependent and independent mechanisms in DLBCL. Silencing of YB-1 could sensitize DLBCL cells to mitoxantrone and overcome cell adhesion-mediated drug resistance (CAM-DR) phenotype in an AKT-dependent manner.
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Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/patologia , Proteína 1 de Ligação a Y-Box/metabolismo , Adesão Celular/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitoxantrona/farmacologia , Análise Multivariada , Fosforilação/efeitos dos fármacos , Fosfosserina/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Previous studies have shown that chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) exerts its anti-apoptotic function in many solid cancers. However, its role in human multiple myeloma (MM) has not been thoroughly elucidated. In this study, we investigate the role of CHD1L in MM. Preliminarily, up-regulation and down-regulation assay verified that CHD1L exerts its anti-apoptotic role through the apoptotic pathway involving caspase-9-caspase-3 apoptotic pathway in MM cells. In addition, we determined that CHD1L expression is increased when MM cells were adhered to fibronectin (FN) or bone marrow stromal cell line HS-5 cells and cell adhesion assay indicated that CHD1L siRNA reversed the high cell adhesion rate. Consistent with the reduced adhesion rate, the cells translated to a compromised cell adhesion-mediated drug resistance (CAM-DR) phenotype in MM. In summary, we will propose strategies for developing a CHD1L inhibitor for potential treatment of MM.
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Adesão Celular/fisiologia , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Mieloma Múltiplo/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Células da Medula Óssea , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , RNA Interferente Pequeno/farmacologia , Células Estromais , Regulação para CimaRESUMO
OBJECTIVE: Vaccinia-related kinase 1 (VRK1) has been reported to participate in the development of a variety of tumors. However, the role of VRK1 in multiple myeloma (MM) has not been investigated. The present study was undertaken to determine the expression and biologic function of VRK1 in human MM. METHODS: First, we constructed a model of cell adhesion in MM, the mRNA and protein level of VRK1 in suspension and adhesion model was analyzed by RT-PCR and western blot. Then, flow cytometry assay and western blot were used to investigate the mechanism of VRK1 in the proliferation of MM cells. In vitro, following using shRNA interfering VRK1 expression, we performed adhesion assay and cell viability assay to determine the effect of VRK1 on adhesive rate and drug sensitivity. RESULTS: VRK1 was lowly expressed in adherent MM cells and highly expressed in suspended cells. In addition, VRK1 was positively correlated with the proliferation of MM cells by regulating the expression of cell cycle-related protein, such as cyclinD1, CDK2 and p27kip1. Furthermore, VRK1 could reverse cell adhesion mediated drug resistance (CAM-DR) by down-regulating the ability of cell adhesion. CONCLUSION AND DISCUSSION: Our data supports a role for VRK1 in MM cell proliferation, adhesion, and drug resistance, and it may pave the way for a novel therapeutic approach for CAM-DR in MM.
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Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Mieloma Múltiplo/enzimologia , Proteínas Serina-Treonina Quinases/biossíntese , Antineoplásicos/farmacologia , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Inibidor de Quinase Dependente de Ciclina p27/biossíntese , Inibidor de Quinase Dependente de Ciclina p27/genética , Resistencia a Medicamentos Antineoplásicos , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mitoxantrona/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , TransfecçãoRESUMO
The chaperonin containing t-complex polypeptide 1 (CCT) is known to mediate folding of proteins. CCT, subunit 8 (CCT8), is the θ subunit of CCT complex chaperonin. CCT8 has been reported to be dysregulated in several tumor tissues. In this study, we investigated the role of CCT8 in B-cell non-Hodgkin's lymphoma (NHL). Clinically, the expression levels of CCT8 in reactive lymphoid hyperplasia (RLH) and B-cell NHL specimens were investigated using immunohistochemical analysis. We found that CCT8 was highly expressed in proliferating germinal center cells compared with the quiescent cells of the follicular mantle zone. Furthermore, CCT8 was highly expressed in progressive lymphomas than in indolent lymphomas. Kaplan-Meier curve showed that high expression of CCT8 was significantly associated with shorter overall survival in patients with diffuse large B-cell lymphoma. Moreover, we demonstrated that CCT8 could promote the proliferation of B-cell NHL cells. In addition, we found that CCT8 could accelerate the G1/S transition in B-cell NHL. Finally, we demonstrated that overexpression of CCT8 could reverse cell adhesion-mediated drug resistance (CAM-DR) phenotype. Our study may shed new insights into the important role of CCT8 in cancer development.
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Chaperonina com TCP-1/fisiologia , Linfoma de Células B/química , Idoso , Adesão Celular , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Chaperonina com TCP-1/análise , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Centro Germinativo/química , Centro Germinativo/patologia , Humanos , Imuno-Histoquímica/métodos , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Previous studies have demonstrated that Homer1b/c plays an important pro-apoptotic role through classical mitochondrial apoptotic pathway. The present study was undertaken to determine the expression and functional significance of Homer1b/c in multiple myeloma (MM). We found that Homer1b/c was lowly expressed in MM cell apoptotic model induced by doxorubicin. The positive role of Homer1b/c in cell apoptosis was further confirmed by knocking down Homer1b/c. Further study confirmed that Homer1b/c was able to affect the CAM-DR via pro-apoptotic activity regulating the ability of cell adhesion. Collectively, these data indicate that Homer1b/c may represent a good candidate for pursuing clinical trial in MM.
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Proteínas de Transporte/biossíntese , Resistencia a Medicamentos Antineoplásicos/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Apoptose/efeitos dos fármacos , Proteínas de Transporte/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Arcabouço Homer , Humanos , Mieloma Múltiplo/patologiaRESUMO
Recent studies have identified that thyroid hormone receptor-interacting protein 6 (TRIP6) is implicated in tumorigenesis. However, the functional role of TRIP6 in non-Hodgkin's lymphoma (NHL) has never been elucidated. In this study, we demonstrated that TRIP6 is reversely correlated with the clinical outcomes of NHL patients. Western blot and immunohistochemical analysis revealed that TRIP6 expression is lower in indolent lymphoma than in progressive lymphoma. Kaplan-Meier survival curves indicated that the upregulation of TRIP6 is significantly associated with poor overall survival. Moreover, patients with higher expression of TRIP6 are prone to shorter time to recurrence. Furthermore, we also found that TRIP6 can promote the proliferation of NHL cells via regulating cell cycle progression. In addition, adhesion of lymphoma cells to fibronectin (FN) decreased TRIP6 expression, which led to the upregulation of nuclear p27(Kip1) expression by decreasing phosphorylation of p27(Kip1) at T157. Importantly, overexpression of TRIP6 can reverse cell adhesion-mediated drug resistance (CAM-DR) phenotype in NHL. In summary, these results suggest that TRIP6 is a novel prognostic indicator for NHL patients and may shed new insights into the important role of TRIP6 in cancer development.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Proteínas com Domínio LIM/metabolismo , Linfoma não Hodgkin/metabolismo , Fatores de Transcrição/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Idoso , Adesão Celular , Ciclo Celular , Proliferação de Células , Sobrevivência Celular , Feminino , Citometria de Fluxo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Fenótipo , Prognóstico , Complexo de Endopeptidases do Proteassoma , Resultado do TratamentoRESUMO
BACKGROUND: The Karyopherin proteins are involved in the shuttling of cargo proteins, and certain RNAs, across the nuclear pore complex into and out of the cell nucleus. Karyopherin ß1 (Kpnß1) is a member of the Karyopherin ß superfamily of nuclear transport proteins. In addition to the nuclear import function, Kpnß1 is associated with the occurrence of tumors. This study investigated the expression and biologic function of Kpnß1 in diffuse large B-cell lymphoma (DLBCL). METHODS: The prognostic value of Kpnß1 expression was evaluated using immunohistochemical staining. The role of Kpnß1 on cell proliferation- and cell adhesion-mediated drug resistance (CAM-DR) was also determined. RESULTS: We demonstrated that Kpnß1 mRNA and protein expression levels were significantly higher in DLBCL B-cells and DLBCL cell lines than in normal CD19 purified B-cells. Immunohistochemical analysis suggested that the expression of Kpnß1 was correlated with Ki-67 (P < 0.001). Kaplan-Meier curve showed that high expression of Kpnß1 was significantly associated with shorter overall survival. In addition, Kpnß1 was associated with the proliferation of DLBCL cells. Importantly, we found that Kpnß1 could interact with p65 and promote CAM-DR via accelerating NF-κB activation in DLBCL. CONCLUSIONS: Patients with tumors highly expressing Kpnß1 have poorer overall survivals. Kpnß1 interacts with p65 and enhances CAM-DR.
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Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , beta Carioferinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Adesão Celular/genética , Linhagem Celular Tumoral , Feminino , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Regulação para Cima , beta Carioferinas/metabolismoRESUMO
OBJECTIVES: Sam68 (Src-associated in mitosis 68 kDa), a substrate for tyrosine kinase c-Src during mitosis, is up-regulated in a variety of human cancers and acts oncogenically promoting tumour progression. This study has explored biological function and clinical significance of Sam68 in non-Hodgkin's lymphoma (NHL). MATERIALS AND METHODS: To examine Sam68 expression in NHL, clinically, eight diffuse large B-cell lymphomas and four reactive lymphoid hyperplasia fresh-frozen tissues were obtained for western blot and quantitative real-time PCR analyses. Using immunohistochemical staining, paraffin wax embedded sections from 164 cases of NHL patients were used to evaluate prognostic value of Sam68. Cell Counting Kit-8 (CCK-8) and soft agar colony assays were conducted to investigate the role of Sam68 in cell viability and cell proliferation respectively. Furthermore, effects of Sam68 on cell adhesion-mediated drug resistance (CAM-DR) was determined by CCK-8 assay and flow cytometric analysis. RESULTS: Expression status of Sam68 inversely correlated with clinical outcomes of patients with NHL, and it was also an independent prognostic factor for the outcomes. In addition, Sam68 was associated with proliferation of NHL cells. Knock-down of its gene inhibited cell proliferation and colony formation by delaying cell cycle progression. Furthermore, OCI-Ly8 and Jeko-1 cells adhering to FN and HS-5 expressed higher Sam68 protein, compared to their suspension counterparts. Sam68 promoted cell adhesion-mediated drug resistance (CAM-DR) via the AKT pathway. CONCLUSIONS: Increased Sam68 expression in NHL resulted in poor prognosis, and it promoted CAM-DR in NHL via AKT.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Adesão Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Resistência a Medicamentos/genética , Linfoma não Hodgkin/genética , Proteínas de Ligação a RNA/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Técnicas de Cocultura , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/biossíntese , Proteínas de Ligação a RNA/metabolismoRESUMO
Cell adhesion mediated drug resistance (CAM-DR) remains the major barrier in human multiple myeloma (MM) therapy. In the present study, we aimed at investigating the role of pyruvate kinase isoform M2 (PKM2) in MM CAM-DR. We determined that PKM2 expression was positively correlated with cell proliferation and knockdown of PKM2 contributed to the increased cell adhesion rate in MM. The enhancement in the adhesion of MM cells to fibronectin or the bone marrow stroma cell line HS-5 cells translated to an increased CAM-DR phenotype. Importantly, we showed that this CAM-DR phenotype was correlated with the phosphorylation of Akt and ERK in MM cells. Taken together, our data shed new light on the molecular mechanism of CAM-DR in MM, and targeting PKM2 may be a novel therapeutic approach for improving the effectiveness of chemotherapy in MM.
Assuntos
Proteínas de Transporte/fisiologia , Proteínas de Membrana/fisiologia , Mieloma Múltiplo/enzimologia , Proteínas de Neoplasias/fisiologia , Hormônios Tireóideos/fisiologia , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Adesão Celular , Divisão Celular , Linhagem Celular Tumoral , Técnicas de Cocultura , Inibidor de Quinase Dependente de Ciclina p27/biossíntese , Inibidor de Quinase Dependente de Ciclina p27/genética , Resistencia a Medicamentos Antineoplásicos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibronectinas , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Transdução de Sinais/fisiologia , Células Estromais , Hormônios Tireóideos/biossíntese , Hormônios Tireóideos/genética , Proteínas de Ligação a Hormônio da TireoideRESUMO
DYRK2, a dual-specificity tyrosine-(Y)-phosphorylation regulated kinase gene, is involved in regulating many processes such as cell proliferation, cell differentiation and cytokinesis. DYRK2 also plays an important role in many cancers, such as breast cancer, non-small cell lung cancer and esophageal adenocarcinomas. In this study, we found that DYRK2 is associated with the proliferation of Non-Hodgkin's lymphoma (NHL) and cell adhesion mediated drug resistance (CAM-DR). Clinically, the mRNA and protein expression levels of DYRK2 are decreased in NHL tissues compared with reactive lymphoid hyperplasia tissues. Immunohistochemical analysis revealed that low expression of DYRK2 is associated with poor prognosis of NHL patients. Interestingly, knockdown of DYRK2 can promote cell proliferation via modulating cell cycle progression. Finally, we demonstrated that DYRK2 plays an important role in CAM-DR by regulating p27(Kip1) expression. Importantly, DYRK2 knockdown reverses CAM-DR in NHL. Our research suggested that DYRK2 may be a novel therapeutic target for NHL.
Assuntos
Adesão Celular , Resistencia a Medicamentos Antineoplásicos , Inativação Gênica , Linfoma não Hodgkin/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Adulto , Idoso , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p27 , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Fenótipo , Fosforilação , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , RNA Interferente Pequeno/genética , Quinases DyrkRESUMO
ErbB3 binding protein-1 (EBP1) belongs to a family of DNA/RNA binding proteins implicated in cell growth, differentiation and apoptosis. Previous data demonstrated that EBP1 regulates phosphorylation of Akt to drive tumor progress. However, the expression and biological functions of EBP1 in ulcerative colitis (UC) remain unclear. In this study, we reported for the first time that EBP1 was down-regulated in intestinal epithelial cell (IECs) of patients with UC. In DSS-induced colitis, we observed the down-regulation of EBP1 accompanied with the elevated levels of proinflammatory cytokines (IL-1ß, IL-6 and IL-8) and Akt activation indicators (phosphorylated Akt) in colitis IECs, indicating the possible involvement of EBP1 in regulation of intestinal inflammation via mediating Akt in UC. Employing the TNF-α-treated HT-29 cells as an IEC inflammatory model, we confirmed the negative correlation of EBP1 with Akt activation and Akt-dependent inflammation progress in vitro. EBP1 knocking down and over-expression significantly regulated TNF-α-induced Akt activation and proinflammatory cytokines expression in HT-29 cells. Taken together, our data suggested that EBP1 participates in the regulation of intestinal inflammation via mediating Akt signaling pathway.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Intestinos/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Sulfato de Dextrana , Regulação para Baixo/efeitos dos fármacos , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Enterócitos/patologia , Ativação Enzimática/efeitos dos fármacos , Feminino , Células HT29 , Humanos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
Enolases are glycolytic enzymes responsible for the ATP-generated conversion of 2-phosphoglycerate to phosphoenolpyruvate. In addition to the glycolytic function, Enolase 1 (ENO1) has been reported up-regulation in several tumor tissues. In this study, we investigated the expression and biologic function of ENO1 in Non-Hodgkin's Lymphomas (NHLs). Clinically, by western blot analysis we observed that ENO1 expression was apparently higher in diffuse large B-cell lymphoma than in the reactive lymphoid tissues. Subsequently, immunohistochemical staining of 144 NHLs suggested that the expression of ENO1 was significantly lower in the indolent lymphomas compared with the progressive lymphomas. Further, we identified ENO1 as an independent prognostic factor, and it was significantly correlated with overall survival of NHL patients. In addition, we found that ENO1 could promote cell proliferation, regulate cell cycle associated gene and PI3K/AKT signaling pathway in NHLs. Finally, we verified that ENO1 participated in the process of lymphoma cell adhesion mediated drug resistance (CAM-DR). Adhesion to FN or HS5 cells significantly protected OCI-Ly8 and Daudi cells from cytotoxicity compared with those cultured in suspension, and these effects were attenuated when transfected with ENO1-siRNA. Based on the study, we propose that inhibition of ENO1 expression may be a novel strategy for therapy for NHLs patients, and it may be a target for drug resistance.
Assuntos
Biomarcadores Tumorais/fisiologia , Adesão Celular , Proliferação de Células , Proteínas de Ligação a DNA/fisiologia , Linfoma não Hodgkin/enzimologia , Fosfopiruvato Hidratase/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Transdução de SinaisRESUMO
The expression and biologic function of the gene encoding vacuolar protein sorting 4B (VPS4B) in human multiple myeloma (MM) were investigated in this study. We determined that VPS4B expression is decreased in adherent MM cells and that knockdown of VPS4B expression induces cell adhesion-mediated drug resistance (CAM-DR) in MM. This induced CAM-DR phenotype manifested through down-regulation of cell apoptosis and requires phosphorylation of AKT and Erk. Finally, VPS4B expression was positively correlated with cell proliferation. Our findings support a role for VPS4B in MM cell proliferation, adhesion, and drug resistance, and pave the way for a novel therapeutic approach targeting this molecule.
Assuntos
Adenosina Trifosfatases/genética , Resistencia a Medicamentos Antineoplásicos/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/genética , ATPases Associadas a Diversas Atividades Celulares , Adenosina Trifosfatases/metabolismo , Apoptose/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Fenótipo , Fosforilação , Proteínas Proto-Oncogênicas c-aktRESUMO
The expression and biologic function of SGTA in Non-Hodgkin's Lymphomas (NHL) was investigated in this study. Clinically, by immunohistochemistry analysis we detected SGTA expression in both reactive lymphoid tissues and NHL tissues. In addition, we also correlated high expression of SGTA with poor prognosis. Functionally, SGTA expression was positively related with cell proliferation and negative related with cell adhesion. Finally, SGTA knockdown induced adhesion-mediated drug resistance. Our finding supports a role of SGTA in NHL cell proliferation, adhesion and drug resistance, and it may pave the way for a novel therapeutic approach for CAM-DR in NHL.