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1.
J Biomed Sci ; 29(1): 69, 2022 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-36100865

RESUMEN

The tripartite motif (TRIM) protein family is a highly conserved group of E3 ligases with 77 members known in the human, most of which consist of a RING-finger domain, one or two B-box domains, and a coiled-coil domain. Generally, TRIM proteins function as E3 ligases to facilitate specific proteasomal degradation of target proteins. In addition, E3 ligase independent functions of TRIM protein were also reported. In hepatocellular carcinoma, expressions of TRIM proteins are both regulated by genetic and epigenetic mechanisms. TRIM proteins regulate multiple biological activities and signaling cascades. And TRIM proteins influence hallmarks of HCC. This review systematically demonstrates the versatile roles of TRIM proteins in HCC and helps us better understand the molecular mechanism of the development and progression of HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/genética , Proteínas , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
2.
Biochem Biophys Res Commun ; 521(4): 984-990, 2020 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-31727371

RESUMEN

Diabetic nephropathy (DN) is among the common complications of diabetes and is a major cause of end-stage kidney disease. Emerging data indicate that renal inflammation is involved in DN progression and aggravation. Still, the exact cellular mechanisms remain unclear. Dysregulated expression of microRNAs (miRNAs) is associated with multiple diseases, including DN. The relationship between miRNAs and inflammation in DN is also unexplored. Here, we evaluated the role of miR-485 in mediating the response of human mesangial cells (HMCs) to a high glucose (HG) concentration, and the potential underlying mechanism. We found that miR-485 expression is significantly decreased in HG-stimulated HMCs. Overexpression of miR-485 suppressed HG-induced proliferation of HMCs. Lower production of proinflammatory cytokines (i.e., TNF-α, IL-1ß, and IL-6) was observed in miR-485-overexpressing HMCs. Overexpression of miR-485 markedly suppressed the overexpression of extracellular-matrix proteins, e.g., collagen IV (Col IV) and fibronectin (FN), in HG-stimulated HMCs. Furthermore, miR-485 suppressed the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 5 (NOX5), restrained the HG-induced HMC proliferation, downregulated the expression of proinflammatory cytokines, and inhibited the production of extracellular-matrix proteins in HMCs. These results provide new insights into the involvement of the miR-485-NOX5 signaling pathway in DN progression.


Asunto(s)
Nefropatías Diabéticas/genética , Inflamación/genética , Inflamación/patología , Células Mesangiales/metabolismo , Células Mesangiales/patología , MicroARNs/metabolismo , Modelos Biológicos , NADPH Oxidasa 5/metabolismo , Secuencia de Bases , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Nefropatías Diabéticas/patología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/toxicidad , Células HEK293 , Humanos , Células Mesangiales/efectos de los fármacos , MicroARNs/genética , Estrés Oxidativo/efectos de los fármacos
3.
Proc Natl Acad Sci U S A ; 114(41): E8685-E8694, 2017 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-28973887

RESUMEN

The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/ß1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/ß1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/ß1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and ß1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/ß1 complex to maintain the high-affinity ß1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/ß1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced α5 integrin from ß1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5ß1. Thus, tumor cells adapt to microenvironmental stressors induced by metastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/ß1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.


Asunto(s)
Neoplasias de la Mama/secundario , Resistencia a Antineoplásicos , Glioblastoma/secundario , Integrina beta1/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Inhibidores de la Angiogénesis/farmacología , Animales , Apoptosis/efectos de los fármacos , Bevacizumab/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Femenino , Fibronectinas/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Humanos , Integrina beta1/genética , Ratones , Invasividad Neoplásica , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-met/genética , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Biochem Biophys Res Commun ; 503(2): 977-983, 2018 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-29932921

RESUMEN

Emerging evidence has shown that microRNAs (miRNAs) play a mediatory role in the pathogenesis of diabetic nephropathy (DN), but the function of the involved miRNAs is still incomplete. Here, we found that miR-455-3p was down-regulated in the human mesangial cells (HMC) and human proximal tubule epithelial cells (HK-2) stimulated with high glucose (HG) or transforming growth factor beta 1 (TGF-ß1). Rho-associated coiled coil-containing protein kinase 2 (ROCK2) was identified as a directed target of miR-455-3p. Overexpression of ROCK2 significantly attenuated the inhibitory effects of miR-455-3p on cell proliferation, extracellular matrix (ECM) synthesis and epithelial-mesenchymal transition (EMT) in HG-treated cells. Furthermore, the DN model was prepared by using high-fat feeding combined with Streptozotocin (STZ) induced rats, and the DN group was treated by injecting miR-455-3p agomir. The results of periodic acid-Schiff (PAS) and Masson staining showed that miR-455-3p overexpression improved the pathological changes of glomerular hypertrophy, mesangial amplification, and renal fibrosis. Additionally, miR-455-3p overexpression decreased ROCK2, proliferating cell nuclear antigen (PCNA) and Collagen I levels, and also reduced inflammatory cytokines TNF-α, MCP-1 and IL-1ß levels in vivo. Altogether, these results suggest that miR-455-3p plays an essential role in the treatment of renal fibrosis through repressing ROCK2 expression; and miR-455-3p might be an effective therapy for DN.


Asunto(s)
Nefropatías Diabéticas/genética , Regulación hacia Abajo , Riñón/patología , MicroARNs/genética , Quinasas Asociadas a rho/genética , Animales , Línea Celular , Proliferación Celular , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/terapia , Transición Epitelial-Mesenquimal , Fibrosis , Terapia Genética , Humanos , Masculino , Ratas Sprague-Dawley , Regulación hacia Arriba
5.
Cell Physiol Biochem ; 42(2): 594-602, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28954270

RESUMEN

BACKGROUND/AIMS: The diagnosis of type 2 diabetic nephropathy (T2DN) patients is important to prevent the long-term damaging effects of kidney loss in patients with diabetes and is decisive for patient outcomes. The aim of this study was to explore urine retinol binding protein (RBP) and neutrophil gelatinase-associated lipocalin (NGAL) in T2DN patients with and without albuminuria. METHODS: A total of 293 T2DN patients were divided into three groups according to their urine albumin/urine creatinine ratio (UACR): normoalbuminuria group (UACR<30 mg/g, n=100), microalbuminuria group (UACR 30-300 mg/g, n=100) and macroalbuminuria group (UACR>300 mg/g, n=93); 50 non-diabetic subjects were recruited as the control group. The levels of urine RBP, NGAL, TNF-α and IL-18 in T2DN patients and non-diabetic subjects were measured using ELISA assays. RESULTS: We first analyzed the clinical characteristics of the control and T2DN groups and found that urine NGAL, RBP, TNF-α and IL-18 levels were significantly increased and significantly correlated with the degree of albuminuria. In addition, univariate linear regression analysis showed that urine RBP was associated with UACR, BMI, Scr, BUN, TG, disease duration, SBP, NGAL, TNF-α and IL-18 levels, and urine NGAL was positively correlated with UACR, Scr, BUN, RBP, TNF-α and IL-18 levels. CONCLUSION: The results indicate that urine levels of NGAL and RBP may be independently associated with albuminuria in T2DN and may serve as novel biomarkers for the identification of T2DN.


Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/orina , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/orina , Lipocalina 2/orina , Proteínas de Unión al Retinol/orina , Anciano , Anciano de 80 o más Años , Albuminuria/complicaciones , Albuminuria/orina , Biomarcadores/orina , Nefropatías Diabéticas/diagnóstico , Femenino , Humanos , Interleucina-18/orina , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/orina
6.
BMC Cancer ; 15: 62, 2015 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-25884851

RESUMEN

BACKGROUND: Given the paucity of information on dose intensity, the objective of this study is to describe the use of adjuvant chemotherapy for stage III colon cancer, focusing on relative dose intensity (RDI), overall survival (OS) and disease-free survival (DFS). METHODS: Retrospective cohort of 367 patients diagnosed with stage III colon cancer in 2003-2008 and treated at 19 VA medical centers. Kaplan-Meier curves summarize 5-year OS and 3-year DFS by chemotherapy regimen and RDI, and multivariable Cox proportional hazards regression was used to model these associations. RESULTS: 5-fluorouracil/leucovorin (FU/LV) was the most commonly initiated regimen in 2003 (94.4%) and 2004 (62.7%); in 2005-2008, a majority of patients (60%-74%) was started on an oxaliplatin-based regimen. Median RDI was 82.3%. Receipt of >70% RDI was associated with better 5-year OS (p < 0.001) and 3-year DFS (P = 0.009) than was receipt of ≤70% RDI, with 5-year OS rates of 66.3% and 50.5%, respectively and 3-year DFS rates of 66.1% and 52.7%, respectively. In the multivariable analysis of 5-year OS, oxaliplatin + 5-FU/LV (versus 5-FU/LV) (HR = 0.55; 95% CI = 0.34-0.91), >70% RDI at the first year (HR = 0.58; 95% CI = 0.37-0.89) and married status (HR = 0.66; 95% CI = 0.45-0.97) were associated with significantly decreased risk of death, while age ≥75 (versus 55-64) (HR = 2.06; 95% CI = 1.25-3.40), Charlson Comorbidity Index (HR = 1.17; 95% CI = 1.06-1.30), T4 tumor status (versus T1/T2) (HR = 5.88; 95% CI = 2.69-12.9), N2 node status (HR = 1.68; 95% CI = 1.12-2.50) and bowel obstruction (HR = 2.32, 95% CI = 1.36-3.95) were associated with significantly increased risk. Similar associations were observed for DFS. CONCLUSION: Patients with stage III colon cancer who received >70% RDI had improved 5-year OS. The association between RDI and survival needs to be examined in studies of adjuvant chemotherapy for colon cancer outside of the VA.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Veteranos , Anciano , Quimioterapia Adyuvante/métodos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento
7.
Cancer Gene Ther ; 31(4): 586-598, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38267623

RESUMEN

Glutamate-NMDAR receptors (GRINs) have been reported to influence cancer immunogenicity; however, the relationship between GRIN alterations and the response to immune checkpoint inhibitors (ICIs) has not been determined. This study combined clinical characteristics and mutational profiles from multiple cohorts to form a discovery cohort (n = 901). The aim of this study was to investigate the correlation between the mutation status of the GRIN gene and the response to ICI therapy. Additionally, an independent ICI-treated cohort from the Memorial Sloan Kettering Cancer Center (MSKCC, N = 1513) was used for validation. Furthermore, this study explored the associations between GRIN2A mutations and intrinsic and extrinsic immunity using multiomics analysis. In the discovery cohort, patients with GRIN2A-MUTs had improved clinical outcomes, as indicated by a higher objective response rate (ORR: 36.8% vs 25.8%, P = 0.020), durable clinical benefit (DCB: 55.2% vs 38.7%, P = 0.005), prolonged progression-free survival (PFS: HR = 0.65; 95% CI 0.49 to 0.87; P = 0.003), and increased overall survival (OS: HR = 0.67; 95% CI 0.50 to 0.89; P = 0.006). Similar results were observed in the validation cohort, in which GRIN2A-MUT patients exhibited a significant improvement in overall survival (HR = 0.66; 95% CI = 0.49 to 0.88; P = 0.005; adjusted P = 0.045). Moreover, patients with GRIN2A-MUTs exhibited an increase in tumor mutational burden, high expression of costimulatory molecules, increased activity of antigen-processing machinery, and infiltration of various immune cells. Additionally, gene sets associated with cell cycle regulation and the interferon response were enriched in GRIN2A-mutated tumors. In conclusion, GRIN2A mutation is a novel biomarker associated with a favorable response to ICIs in multiple cancers.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Interferones , Mutación , Biomarcadores de Tumor/genética
8.
Curr Mol Pharmacol ; 2023 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-37881074

RESUMEN

BACKGROUND: Cholangiopathies comprise a spectrum of diseases without curative treatments. Pharmacological treatments based on bile acid (BA) metabolism regulation represent promising therapeutic strategies for the treatment of cholangiopathies. Gentiopicroside (GPS), derived from the Chinese medicinal herb Gentianae Radix, exerts pharmacological effects on bile acid metabolism regulation and oxidative stress. OBJECTIVE: The present study aims to investigate the effect of GPS on 3,5-diethoxycarbonyl-1,4dihydrocollidine (DDC)-induced cholangiopathy. METHODS: Two independent animal experiments were designed to evaluate the comprehensive effect of GPS on chronic DDC diet-induced cholangiopathy, including bile duct obliteration, ductular reaction, BA metabolism reprogramming, liver fibrosis, oxidative stress and inflammatory responses. RESULTS: In the first pharmacological experiment, three doses of GPS (5, 25 and 125 mg/kg) were injected intraperitoneally into mice fed a DDC diet for 14 days. DDC induced a typical ductular reaction, increased periductal fibrosis and mixed inflammatory cell infiltration in the portal areas. GPS treatment showed dose-dependent improvements in the ductular reaction, BA metabolism, fibrosis, oxidative stress and inflammatory response. In the second experiment, a high dose of GPS was injected intraperitoneally into control mice for 28 days, resulting in no obvious histologic changes and significant serologic abnormalities in liver function. However, GPS inhibited DDC-induced oxidative stress, serum and hepatic BA accumulation, proinflammatory cytokine production, and immunocyte infiltration. Specifically, the GPS-treated groups showed decreased infiltration of monocyte-derived macrophages and CD4+ and CD8+ T lymphocytes, as well as preserved Kupffer cells. CONCLUSION: GPS alleviated chronic DDC diet-induced cholangiopathy disorder by improving the ductular reaction, periductal fibrosis, oxidative stress and inflammatory response. Its dosage-dependent pharmacological effects indicated that GPS warrants its further evaluation in clinical trials for cholangiopathy.

9.
J Tradit Complement Med ; 13(4): 345-357, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37396159

RESUMEN

Purpose: Cholestatic liver diseases are groups of hepatobiliary diseases without curative drug-based therapy options. Regulation of bile acid (BA) metabolism, hepatoperiductal fibrosis, and inflammatory response indicated present novel methods for the treatment of cholestatic liver disease. Costunolide (COS) from herb Saussurea lappa exerts a pharmacological effect of regulation of BA metabolism, liver fbrosis and inflammatory response. The present study aimed to clarify the pharmacodynamic effects of COS against the murine model of cholestatic liver disease. Methods: We established a murine model of cholestatic liver disease through chronic feeding of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 28 days. Two independent in vivo experiments were designed to reveal the pharmacological effect of COS against cholestatic liver disease. In the first experiment, two dosages of COS (10 and 30 mg/kg) were intraperitoneally injected into model mice daily for 14 days. In the second experiment, high dosage of COS (30 mg/kg) was intraperitoneally injected into control and model mice daily for 28 days. Results: In the evaluation of the hepatoprotective effect of COS, COS showed dosage-dependent improvement of cholestatic liver disease, including ductular reaction, hepatoperiductal fibrosis, and inflammatory response. The mechanism of COS-mediated hepatoprotective effects mainly relies on the regulation of BA metabolism, and the inflammatory response. DDC diet feed induced hepatic BA metabolism, transport and circulation dysfunction. COS treatment not only regulated the BA metabolism and transport gene, but also reprogrammed hepatic primary and secondary BA concentrations. DDC induced hepatic infiltrated monocytes derived macrophages and lymphocytes were inhibited, while Kupffer cells were preserved by COS treatment. The liver elevating inflammatory cytokines of DDC diet feed were alleviated by COS. Moreover, high dosage of 30 mg/kg COS treatment for 28 days resulted in no significant serological changes and no obvious hepatic histopathological changes when compared with control mice. Conclusion: COS protected against DDC diet feeding-induced cholestatic liver disease since COS regulated BA metabolism, ductular reaction, hepatoperiductal fibrosis and inflammatory response. COS is suggested as a potential natural product for the treatment of cholestatic liver disease.

10.
Exp Cell Res ; 317(6): 838-48, 2011 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-21211535

RESUMEN

High levels of the soluble form of E-cadherin can be found in the serum of cancer patients and are associated with poor prognosis. Despite the possible predictive value of soluble E-cadherin, little is understood concerning its patho-physiological consequences in tumor progression. In this study, we show that soluble E-cadherin facilitates cell survival via functional interaction with cellular E-cadherin. Exposure of cells to a recombinant form of soluble E-cadherin, at a concentration found in cancer patient's serum, prevents apoptosis due to serum/growth factor withdrawal, and inhibits epithelial lumen formation, a process that requires apoptosis. Further, soluble E-cadherin-mediated cell survival involves activation of the epidermal growth factor receptor (EGFR) and EGFR-mediated activation of both phosphoinositide-3 kinase (PI3K)/AKT and ERK1/2 signaling pathways. These results are evidence of a complex functional interplay between EGFR and E-cadherin and also suggest that the presence of soluble E-cadherin in cancer patients' sera might have relevance to cell survival and tumor progression.


Asunto(s)
Apoptosis/efectos de los fármacos , Cadherinas/farmacología , Receptores ErbB/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Cadherinas/metabolismo , Supervivencia Celular/efectos de los fármacos , Células HEK293 , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteína Oncogénica v-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Solubilidad
11.
Cell Oncol (Dordr) ; 45(1): 163-178, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35089546

RESUMEN

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world with a high mortality rate. Receptor tyrosine kinases play important roles in the occurrence and development of various cancers. Discoid protein domain receptor 1 (DDR1) is a special type of transmembrane receptor tyrosine kinase. Here, we show that the expression of DDR1 is significantly increased in HCC and is related to a poor clinical prognosis. METHODS: The expression of DDR1 in HCC cell lines and primary HCC specimens was evaluated using Western blotting and immunohistochemistry. A correlation between DDR1 and SLC1A5 expression was also investigated in primary HCC specimens. Cell proliferation was evaluated using in vitro CCK8 and colony formation assays. Gene knock-down and overexpression assays, CHX, NH4CL and Mg132 interference tests and immunoprecipitation, as well as nude mouse xenograft models were used to assess the mechanism by which DDR1 promotes tumorigenesis in vitro and in vivo. RESULTS: We found that DDR1 promotes the proliferation of HCC cells and accelerates the growth of HCC tumor xenografts, while DDR1 downregulation had the opposite effect. We also found that loss or gain of DDR1 expression affected HCC cell cycle progression. Mechanistically, we found that DDR1 interacts with SLC1A5, which belongs to the solute carrier (SLC) family of transporters, and regulates its stability, thereby affecting the mTORC1 signaling pathway. In addition, we found that SLC1A5 regulation by DDR1 can be restored by lysosome inhibitors. We also found that DDR1 is highly expressed in HCC tissues and that increased DDR1 expression predicts a shorter overall survival (OS) time. We additionally found that the expression of SLC1A5 was positively correlated with that of DDR1. Together, our data indicate that DDR1 acts as a tumor-promoting factor that can control HCC cell proliferation and cell cycle progression by stabilizing SLC1A5 in a lysosome-dependent way. CONCLUSIONS: Our study reveals a new mechanism by which DDR1 plays a liver cancer-promoting role. We also found that DDR1 expression serves as an independent prognostic marker, and that DDR1 and SLC1A5 expression levels are positively correlated in clinical samples. Our findings provide a new perspective for understanding HCC development and offers new targets for the treatment and management of HCC.


Asunto(s)
Sistema de Transporte de Aminoácidos ASC , Carcinoma Hepatocelular , Receptor con Dominio Discoidina 1/metabolismo , Neoplasias Hepáticas , Sistema de Transporte de Aminoácidos ASC/genética , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular , Receptor con Dominio Discoidina 1/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Antígenos de Histocompatibilidad Menor , Transducción de Señal
12.
Mol Cancer Ther ; 18(9): 1565-1576, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31270152

RESUMEN

Amplification of the epidermal growth factor receptor gene (EGFR) represents one of the most commonly observed genetic lesions in glioblastoma (GBM); however, therapies targeting this signaling pathway have failed clinically. Here, using human tumors, primary patient-derived xenografts (PDX), and a murine model for GBM, we demonstrate that EGFR inhibition leads to increased invasion of tumor cells. Further, EGFR inhibitor-treated GBM demonstrates altered oxidative stress, with increased lipid peroxidation, and generation of toxic lipid peroxidation products. A tumor cell subpopulation with elevated aldehyde dehydrogenase (ALDH) levels was determined to comprise a significant proportion of the invasive cells observed in EGFR inhibitor-treated GBM. Our analysis of the ALDH1A1 protein in newly diagnosed GBM revealed detectable ALDH1A1 expression in 69% (35/51) of the cases, but in relatively low percentages of tumor cells. Analysis of paired human GBM before and after EGFR inhibitor therapy showed an increase in ALDH1A1 expression in EGFR-amplified tumors (P < 0.05, n = 13 tumor pairs), and in murine GBM ALDH1A1-high clones were more resistant to EGFR inhibition than ALDH1A1-low clones. Our data identify ALDH levels as a biomarker of GBM cells with high invasive potential, altered oxidative stress, and resistance to EGFR inhibition, and reveal a therapeutic target whose inhibition should limit GBM invasion.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Familia de Aldehído Deshidrogenasa 1/metabolismo , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dasatinib/farmacología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib/farmacología , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Ratones , Estrés Oxidativo/efectos de los fármacos , Retinal-Deshidrogenasa/metabolismo
13.
N Engl J Med ; 353(19): 2012-24, 2005 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-16282176

RESUMEN

BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. METHODS: We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. RESULTS: Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. CONCLUSIONS: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.


Asunto(s)
Receptores ErbB/genética , Glioblastoma/genética , Fosfohidrolasa PTEN/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Antineoplásicos/uso terapéutico , ADN de Neoplasias/análisis , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib , Femenino , Gefitinib , Amplificación de Genes , Eliminación de Gen , Expresión Génica , Genes erbB-1 , Genes erbB-2 , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Oligodendroglioma/tratamiento farmacológico , Oligodendroglioma/genética , Oligodendroglioma/metabolismo , Fosfohidrolasa PTEN/genética , Reacción en Cadena de la Polimerasa , Quinazolinas/uso terapéutico , Análisis de Secuencia de ADN , Transducción de Señal
14.
Neuro Oncol ; 10(3): 254-64, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18359864

RESUMEN

Glioblastoma multiforme (GBM) is one the most aggressive brain tumors due to the fast and invasive growth that is partly supported by the presence of extensive neovascularization. The matrix metalloproteinase MMP-2 has been associated with invasive and angiogenic properties in gliomas and is a marker of poor prognosis. Since MMP-2 is expressed in both tumor cells and endothelial cells in GBM, we generated genetically engineered MMP-2 knockout (MMP-2ko) GBM to examine the importance of the spatial expression of MMP-2 in tumor and/or normal host-derived cells. MMP-2-dependent effects appeared to be dose-dependent irrespective of its expression pattern. GBM completely devoid of MMP-2 exhibited markedly increased vascular density associated with vascular endothelial growth factor receptor 2 (VEGFR2) activation and enhanced vascular branching and sprouting. Surprisingly, despite the high vascular density, tumor cells were more prone to apoptosis, which led to prolonged survival of tumor-bearing mice, suggesting that the increased vascularity is not functional. Congruently, tumor vessels were poorly perfused, exhibited lower levels of VEGFR2, and did not undergo proper maturation because pericytes of MMP-2ko tumors were not activated and were less abundant. As a result of impaired and dysfunctional angiogenesis, MMP-2ko GBM became more invasive, predominantly by migrating along blood vessels into the brain parenchyma.


Asunto(s)
Neoplasias Encefálicas/enzimología , Glioblastoma/enzimología , Metaloproteinasa 2 de la Matriz/metabolismo , Invasividad Neoplásica , Neovascularización Patológica/enzimología , Animales , Western Blotting , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/patología , Supervivencia Celular/fisiología , Citometría de Flujo , Glioblastoma/irrigación sanguínea , Glioblastoma/patología , Inmunohistoquímica , Hibridación in Situ , Metaloproteinasa 2 de la Matriz/genética , Ratones , Ratones Noqueados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
15.
Nat Cell Biol ; 20(10): 1203-1214, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30202050

RESUMEN

Glioblastoma multiforme (GBMs) are recurrent lethal brain tumours. Recurrent GBMs often exhibit mesenchymal, stem-like phenotypes that could explain their resistance to therapy. Analyses revealed that recurrent GBMs have increased tension and express high levels of glycoproteins that increase the bulkiness of the glycocalyx. Studies showed that a bulky glycocalyx potentiates integrin mechanosignalling and tissue tension and promotes a mesenchymal, stem-like phenotype in GBMs. Gain- and loss-of-function studies implicated integrin mechanosignalling as an inducer of GBM growth, survival, invasion and treatment resistance, and a mesenchymal, stem-like phenotype. Mesenchymal-like GBMs were highly contractile and expressed elevated levels of glycoproteins that expanded their glycocalyx, and they were surrounded by a stiff extracellular matrix that potentiated integrin mechanosignalling. Our findings suggest that there is a dynamic and reciprocal link between integrin mechanosignalling and a bulky glycocalyx, implying a causal link towards a mesenchymal, stem-like phenotype in GBMs. Strategies to ameliorate GBM tissue tension offer a therapeutic approach to reduce mortality due to GBM.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Glicocálix/metabolismo , Integrinas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Supervivencia Celular/efectos de los fármacos , Retroalimentación Fisiológica/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones Desnudos , Células Madre Neoplásicas/efectos de los fármacos , Tensión Superficial , Temozolomida/uso terapéutico , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Oncogene ; 22(15): 2361-73, 2003 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-12700671

RESUMEN

Epidermal growth factor receptor (EGFR) overexpression occurs in nearly 50% of cases of glioblastoma (GBM), but its clinical and biological implications are not well understood. We have used Affymetrix high-density oligonucleotide arrays to demonstrate that EGFR-overexpressing GBMs (EGFR+) have a distinct global gene transcriptional profile. We show that the expression of 90 genes can distinguish EGFR+ from EGFR nonexpressing (EGFR-) GBMs, including a number of genes known to act as growth/survival factors for GBMs. We have also uncovered two additional novel molecular subtypes of GBMs, one of which is characterized by coordinate upregulation of contiguous genes on chromosome 12q13-15 and expression of both astrocytic and oligodendroglial genes. These results define distinct molecular subtypes of GBMs that may be important in disease stratification, and in the discovery and assessment of GBM treatment strategies.


Asunto(s)
Neoplasias Encefálicas/clasificación , Perfilación de la Expresión Génica , Glioblastoma/clasificación , Análisis de Secuencia por Matrices de Oligonucleótidos , Astrocitos/metabolismo , Astrocitos/patología , Biopsia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Diferenciación Celular , Linaje de la Célula , Cromosomas Humanos Par 12/genética , Receptores ErbB/biosíntesis , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Oligodendroglía/metabolismo , Oligodendroglía/patología , ARN Mensajero/genética , ARN Neoplásico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Técnica de Sustracción , Transcripción Genética
17.
Artículo en Zh | MEDLINE | ID: mdl-26263773

RESUMEN

OBJECTIVE: To understand the characteristics of pro-apoptotic gene SjBAD of Schistosoma japonicum, such as its biology, immunology, and transcriptional expression, and evaluate its potential of the recombinant protein as a vaccine candidate for schistosomiasis. METHODS: SjBAD was amplified by PCR and subeloned into a pET-28a(+) vector, and the recombinant plasmid was transformed into competent E. coli BL21 for producing recombinant protein. The expressions of SjBAD in different development stages of schistosomula and 42-day male and female worms were determined by real-time PCR. The immunogenicity of the recombinant protein was analyzed by Western blotting and ELISA. The potential of this protein as a vaccine candidate molecule was assessed by testing the worm reduction rate and liver egg reduction rate in the BALB/c mice immunized by the recombinant antigen SjBAD. RESULTS: SjBAD was successfully cloned, the recombinant plasmid pET-28a(+)-SjBAD was successfully expressed in E. coli, and the molecular weight of the recombinant protein was around 22 kDa. Western-blotting showed that the recombinant protein had good immunogenicity. The recombinant protein could induce high level of specific IgG antibodies in the BALB/c mice. SjBAD was expressed in all tested 7-, 14-, 21-, 28-, 35- and 42-day worms, and was highly expressed in 14-day schistosomula, while the expression level in 42-day male worms was higher than that in 42-day female worms. Two in- dependent animal trials showed that 30.82% and 27.87% worm reduction rates, as well as 42.52% and 45.84% liver eggs reduction rates were obtained in the rSjBAD vaccinated group compared with those of the blank control group (both P < 0.05). CONCLUSIONS: The proapoptotic gene SjBAD is successfully cloned and expressed. The gene is expressed in different development stages of S. japonicum. The rSjBAD vaccinated BALB/c mice can obtain a partial protective immunity against S. japonicum infection.


Asunto(s)
Schistosoma japonicum/genética , Proteína Letal Asociada a bcl/genética , Animales , Anticuerpos Antihelmínticos/sangre , Femenino , Inmunoglobulina G/sangre , Masculino , Ratones , Ratones Endogámicos BALB C , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Recombinantes/inmunología , Schistosoma japonicum/inmunología , Vacunación , Proteína Letal Asociada a bcl/inmunología
18.
CNS Oncol ; 2(1): 49-65, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23750318

RESUMEN

Angiogenesis inhibitors targeting the VEGF signaling pathway have been US FDA approved for various cancers including glioblastoma (GBM), one of the most lethal and angiogenic tumors. This has led to the routine use of the anti-VEGF antibody bevacizumab in recurrent GBM, conveying substantial improvements in radiographic response, progression-free survival and quality of life. Despite these encouraging beneficial effects, patients inevitably develop resistance and frequently fail to demonstrate significantly better overall survival. Unlike chemotherapies, to which tumors exhibit resistance due to genetic mutation of drug targets, emerging evidence suggests that tumors bypass antiangiogenic therapy while VEGF signaling remains inhibited through a variety of mechanisms that are just beginning to be recognized. Because of the indirect nature of resistance to VEGF inhibitors there is promise that strategies combining angiogenesis inhibitors with drugs targeting such evasive resistance pathways will lead to more durable antiangiogenic efficacy and improved patient outcomes. Further identifying and understanding of evasive resistance mechanisms and their clinical importance in GBM relapse is therefore a timely and critical issue.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Humanos , Transducción de Señal/efectos de los fármacos
19.
Exp Ther Med ; 6(6): 1482-1488, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24250725

RESUMEN

The aim of this study was to investigate the correlation of the proinflammatory marker tumor necrosis factor-α (TNF-α) and the tubular marker neutrophil gelatinase-associated lipocalin (NGAL) with the progression of the early stage of type 2 diabetic nephropathy (DN). Baseline levels of urinary TNF-α and NGAL were measured in 63 non-diabetic controls and 201 patients with type 2 diabetes and different albuminuria statuses. The patients with diabetes (n=125) with normo- or microalbuminuria were subsequently followed-up for 28 (25-32) months, with routine measurements of creatinine and urinary albumin excretion (UAE). It was observed that baseline levels of urinary TNF-α and NGAL were significantly elevated and correlated with the severity of albuminuria in patients with diabetes. During the follow-up, the urinary levels of TNF-α and NGAL were observed to be significantly correlated with a rapid decline in the estimated glomerular filtration rate (eGFR). Following adjustment for other progression promoters, including albuminuria, TNF-α remained a significant predictor of eGFR decline. These results suggest that inflammation is important in the pathogenesis of DN and indicate that TNF-α may be used as an independent predictor for the progression of DN at the early stage.

20.
Artículo en Inglés | MEDLINE | ID: mdl-23589719

RESUMEN

This study aimed to examine the role of GLP-1 in the hypoglycemic activity of wild bitter gourd (Momordica charantia L., BG). In vitro, the GLP-1 secretion in STC-1, a murine enteroendocrine cell line, was dose dependently stimulated by water extract (WE), its fractions (WEL, >3 kD and WES, <3 kD), and a bitter compounds-rich fraction of BG. These stimulations were partially inhibited by probenecid, a bitter taste receptor inhibitor, and by U-73122, a phospholipase C ß 2 inhibitor. These results suggested that the stimulation might involve, at least in part, certain bitter taste receptors and/or PLC ß 2-signaling pathway. Two cucurbitane triterpenoids isolated from BG, 19-nor-cucurbita-5(10),6,8,22-(E),24-pentaen-3 ß -ol, and 5 ß ,19-epoxycucurbita-6,24-diene-3 ß ,23 ξ -diol (karavilagenine E,) showed relative high efficacy in the stimulation. In vivo, mice fed BG diet showed higher insulinogenic index in an oral glucose tolerance test. A single oral dose of WE or WES pretreatment significantly improved intraperitoneal glucose tolerance. A single oral dose of WES significantly decreased glucose and increased insulin and GLP-1 in serum after 30 min. This acute hypoglycemic effect of WES was abolished by pretreatment with exendin-9, a GLP-1 receptor antagonist. Our data provide evidence that BG stimulates GLP-1 secretion which contributes, at least in part, to the antidiabetic activity of BG through an incretin effect.

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