RESUMEN
PURPOSE: To identify biological markers related to the progression and prognosis of GBC. METHODS: The expressions of pyruvate kinase isoenzyme type M2 (PKM2) and activin A receptor type IC (ACVR 1C) in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) were examined using immunohistochemistry. RESULTS: Positive PKM2 and negative ACVR 1C expressions were significantly associated with lymph node metastasis, invasion and TNM stage of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that either elevated PKM2 or loss of ACVR 1C expression significantly correlated with shorter average survival times in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive PKM2 expression and loss of ACVR 1C expression were poor prognosis biomarkers in both SC/ASC and AC patients. CONCLUSIONS: Our study suggested that PKM2 overexpression is a marker of metastasis, invasion and poor prognosis of GBC. ACVR 1C is a tumor suppressor, and lowered ACVR 1C expression is an important marker for the metastasis, invasion, and prognosis of GBC.
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Receptores de Activinas Tipo I/fisiología , Adenocarcinoma/diagnóstico , Biomarcadores de Tumor , Carcinoma Adenoescamoso/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Proteínas Portadoras/fisiología , Neoplasias de la Vesícula Biliar/diagnóstico , Proteínas de la Membrana/fisiología , Hormonas Tiroideas/fisiología , Receptores de Activinas Tipo I/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma Adenoescamoso/metabolismo , Carcinoma Adenoescamoso/mortalidad , Carcinoma Adenoescamoso/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Proteínas Portadoras/metabolismo , Femenino , Neoplasias de la Vesícula Biliar/metabolismo , Neoplasias de la Vesícula Biliar/mortalidad , Neoplasias de la Vesícula Biliar/patología , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Hormonas Tiroideas/metabolismo , Proteínas de Unión a Hormona TiroideRESUMEN
FUNDAMENTO: Quinase Tipo Receptor de Ativina 7 (ALK7) é um tipo de receptor I para a superfamília TGF-β e recentemente apresentou ter uma função importante na manutenção de homeostase metabólica. OBJETIVO: Investigar a associação do polimorfismo do gene ALK7 à síndrome metabólica (SMet) e remodelação cardiovascular em pacientes com SMet. MÉTODOS: O polimorfismo de nucleotídeo único rs13010956 no gene ALK7 foi genotipado em 351 indivíduos chineses submetidos à ultrassonografia cardíaca e das carótidas. As associações do polimorfismo do gene ALK7 ao fenótipo e aos parâmetros da síndrome metabólica e características ultrassônicas cardiovasculares foram analisadas. RESULTADOS: O polimorfismo de rs13010956 no gene ALK7 foi considerado significativamente relacionado ao fenótipo de SMet em mulheres (p < 0,05) e significativamente associado à pressão sanguínea em populações totais (p < 0,05) e femininas (p < 0,01). Outras análises revelaram que rs13010956 estava associado à média da espessura íntima-média de artérias carótidas em mulheres (p < 0,05). Após o controle do índice de massa corporal, pressão arterial, glicemia em jejum e triglicérides, o rs13010956 também foi considerado significativamente associado ao índice de massa do ventrículo esquerdo em populações totais (p < 0,05) e femininas (p < 0,05). CONCLUSÃO: Nossos achados sugeriram que o polimorfismo de rs13010956 do gene ALK7 estava significativamente vinculado ao risco de SMet em mulheres e pode estar envolvido na remodelação cardiovascular em pacientes com SMet.
BACKGROUND: Activin receptor-like kinase 7 (ALK7) is a type I receptor for the TGF-β superfamily and has recently been demonstrated to play an important role in the maintenance of metabolic homeostasis. OBJECTIVE: To investigate the association of the ALK7 gene polymorphism with metabolic syndrome (MetS) and cardiovascular remodeling in MetS patients. METHODS: The single nucleotide polymorphism rs13010956 in the ALK7 gene was genotyped in 351 Chinese subjects undergoing carotid and cardiac ultrasonography. The associations of the ALK7 gene polymorphism with the MetS phenotype, MetS parameters, and cardiovascular ultrasonic features were analyzed. RESULTS: The rs13010956 polymorphism in the ALK7 gene was found to be significantly associated with the MetS phenotype in females (p < 0.05) and was also significantly associated with blood pressure in the total (p < 0.05) and female populations (p < 0.01). Further analysis revealed that rs13010956 was associated with mean intima-media thickness of the carotid arteries in females (p < 0.05). After control for body mass index, blood pressure, fasting blood glucose, and triglycerides, rs13010956 was also found to be significantly associated with left ventricular mass index in the total (p < 0.05) and female populations (p < 0.05). CONCLUSION: Our findings suggested that the ALK7 gene polymorphism rs13010956 was significantly associated with MetS risk in females and may be involved in cardiovascular remodeling in MetS patients.
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Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Receptores de Activinas Tipo I/genética , Síndrome Metabólico/genética , Polimorfismo Genético/genética , Remodelación Ventricular/genética , Receptores de Activinas Tipo I/metabolismo , Grosor Intima-Media Carotídeo , Síndrome Metabólico/metabolismo , Factores de Riesgo , Factores SexualesRESUMEN
BACKGROUND: Activin receptor-like kinase 7 (ALK7) is a type I receptor for the TGF-ß superfamily and has recently been demonstrated to play an important role in the maintenance of metabolic homeostasis. OBJECTIVE: To investigate the association of the ALK7 gene polymorphism with metabolic syndrome (MetS) and cardiovascular remodeling in MetS patients. METHODS: The single nucleotide polymorphism rs13010956 in the ALK7 gene was genotyped in 351 Chinese subjects undergoing carotid and cardiac ultrasonography. The associations of the ALK7 gene polymorphism with the MetS phenotype, MetS parameters, and cardiovascular ultrasonic features were analyzed. RESULTS: The rs13010956 polymorphism in the ALK7 gene was found to be significantly associated with the MetS phenotype in females (p < 0.05) and was also significantly associated with blood pressure in the total (p < 0.05) and female populations (p < 0.01). Further analysis revealed that rs13010956 was associated with mean intima-media thickness of the carotid arteries in females (p < 0.05). After control for body mass index, blood pressure, fasting blood glucose, and triglycerides, rs13010956 was also found to be significantly associated with left ventricular mass index in the total (p < 0.05) and female populations (p < 0.05). CONCLUSION: Our findings suggested that the ALK7 gene polymorphism rs13010956 was significantly associated with MetS risk in females and may be involved in cardiovascular remodeling in MetS patients.
Asunto(s)
Receptores de Activinas Tipo I/genética , Síndrome Metabólico/genética , Polimorfismo Genético/genética , Remodelación Ventricular/genética , Receptores de Activinas Tipo I/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Grosor Intima-Media Carotídeo , Femenino , Humanos , Masculino , Síndrome Metabólico/metabolismo , Persona de Mediana Edad , Factores de Riesgo , Factores Sexuales , Adulto JovenRESUMEN
Transforming growth factor ß1 (TGF-ß1) is a pleiotropic cytokine that modulates cell homeostasis. In Leydig cells, TGF-ß1 exerts stimulatory and inhibitory effect depending on the type I receptor involved in the signaling pathway. The aim of the present work was to study the signaling mechanisms and the intermediates involved in the action of TGF-ß1 on TM3 Leydig cell proliferation in the presence or absence of progesterone. The MTT assay showed that the presence of progesterone in the culture media lead to a proliferative effect that was blocked by Ru 486, an inhibitor of progesterone receptor; and ALK-5 did not participate in this effect. TGF-ß1 (1 ng/ml) increased the expression of p15 (an inhibitor of cell cycle) in TM3 Leydig cells, and this effect was blocked by progesterone (1µM). The expression of PCNA presented a higher increase in the cell cultured with TGF-ß1 plus progesterone than in cells cultured only with TGF-ß1. Progesterone induced the gene expression of endoglin, a cofactor of TGF-ß1 receptor that leads to a stimulatory signaling pathway, despite of the absence of progesterone response element in endoglin gene. In addition, the presence of progesterone induced the gene expression of egr-1 and also KLF14, indicating that this steroid channels the signaling pathway into a non-canonical mechanism. In conclusion, these findings suggest that the proliferative action of TGF-ß1 involves endoglin. This co-receptor might be induced by KLF14 which is probably activated by progesterone.
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Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Células Intersticiales del Testículo/citología , Células Intersticiales del Testículo/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo I/metabolismo , Receptores de Activinas Tipo II , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/metabolismo , ADN Complementario/genética , Endoglina , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células Intersticiales del Testículo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Progesterona/farmacología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Elementos de Respuesta/genética , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
Bovine mammary gland morphogenesis and differentiation are regulated by actions of growth factors including members of the transforming growth factor ß superfamily. Activins A and B, which are members of the transforming growth factor ß superfamily, bind selectively to ActRIB and ActRIIA receptors and their biological effects are antagonized by inhibins and follistatins. In the present paper we evaluated gene and protein expression of the activin and inhibin subunits ßA, ßB, and α-inhibin and follistatin and ActRIB and ActRIIA receptors in the mammary gland of nonpregnant and pregnant heifers. Mammary glands were obtained from nonpregnant Nelore (Bos indicus) heifers (n=9) and from primigravid Nelore heifers during early (n=9), mid (n=6), and late (n=5) pregnancy. Specimens of mammary tissue were analyzed by real-time PCR and immunohistochemistry. The ßA and α-inhibin subunits and ActRIB and ActRIIA mRNA expression was higher in the early-pregnancy group compared with the nonpregnant group. In the mid-pregnancy group, the subunits ßA, ßB, and α-inhibin as much as follistatin mRNA expression was higher compared with the nonpregnant group, whereas ActRIB transcripts were absent in the late-pregnancy group. Immunostaining of these proteins, with the exception of ActRIB, was observed in the mammary tissue sections at all time points analyzed; these findings are in agreement with the observed pattern of mRNA expression. Staining and mRNA expression for ActRIB were undetected in the late-pregnancy group. In summary, the present study demonstrated that the activin-related proteins, ßA, ßB, and α-inhibin subunits, as much as follistatin and ActRIB and ActRIIA receptors display different patterns of expression regarding time of gestation in the bovine mammary gland. The modulation of the expression pattern during gestation suggests that activin-related proteins may play a key role in regulating bovine mammary branching morphogenesis and epithelial differentiation.
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Activinas/metabolismo , Glándulas Mamarias Animales/metabolismo , Embarazo/metabolismo , Receptores de Activinas Tipo I/metabolismo , Receptores de Activinas Tipo II/metabolismo , Animales , Bovinos , Diferenciación Celular , Femenino , Folistatina/metabolismo , Expresión Génica , Edad Gestacional , Subunidades beta de Inhibinas/metabolismo , Inhibinas/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Transforming growth factor beta 1 (TGF-beta1) modulates male reproductive function. Genetically modified mice overexpressing alpha/beta subunits of hCG (hCG+) show Leydig cell hyperplasia/hypertrophy at prepuberty that disappears as the mice approach adulthood. In this study we analyzed the gene expression of TGF-beta1, its specific receptors, type II (TGF-betaRII) and type I (activin receptor-like kinase 1 and 5: ALK1 and ALK5), and co-receptor endoglin (CD105) in purified Leydig cells from hCG+ and wild-type mice at 3 and 8 weeks of age and the occurrence of TGF-beta1, ALK1 and ALK5 by immunohistochemistry. The expression of TGF-beta1 was higher in hCG+ mice at both ages studied, and no changes were observed in TGF-betaRII. ALK5 diminished with age in wild-type mice, whereas ALK1 decreased in hCG+ mice at 8 weeks of age. Endoglin expression showed a marked increase in 3-week-old hCG+ animals. In vitro incubation of Leydig cells from wild-type animals with hCG (10 IU/ml) increased TGF-beta1 and ALK5 expression. Progesterone (10(-6) M) induced endoglin expression. These studies provide novel evidence for differential gene and protein expression of ALK1 and ALK5 at different ages and endoglin expression and hormonal, in purified Leydig cells.
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Gonadotropina Coriónica/farmacología , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Progesterona/farmacología , Factor de Crecimiento Transformador beta1/fisiología , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo I/metabolismo , Receptores de Activinas Tipo II , Factores de Edad , Animales , Células Cultivadas , Gonadotropina Coriónica/genética , Endoglina , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células Intersticiales del Testículo/fisiología , Masculino , Ratones , Ratones Transgénicos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Maduración Sexual/genética , Maduración Sexual/fisiología , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
The aim of this work was to study the ontogeny of chondrocyte cell division using embryo, adult and osteoarthritic (OA) cartilage. We searched for mitosis phases and performed a comparative evaluation of mitotic index, basic fibroblast growth factor b (FGFb), transforming growth factor beta1 (TGF-beta1) receptors, cyclin dependent kinase (CDK1) and Cyclin-B expression in fetal, neonate, 3, 5, 8 weeks old rats and experimental OA. Our results showed that mitosis phases were observed in all normal cartilage studied, although, we found a decrease in mitotic index in relation to tissue development. No mitosis was detected in OA cartilage. We also found a statistical significant reduction in cell number in OA cartilage, compared with the normal tissue. Furthermore, FGFb and TGF-beta1 receptors diminished in relation to tissue development, and were very scarce in experimental OA. Western blot assays showed CDK-1 expression in all cases, including human-OA cartilage. Similar results were observed for Cyclin-B, except for 8 weeks, when it was not expressed. Our results suggest that cell division seems to be scarce, if not absent within the OA cartilage studied. Nevertheless, the existence of factors essential for cell division leaves open the question concerning chondrocyte proliferation in OA cartilage, which is likely to be present in the early stages of the disease.
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Cartílago/embriología , Cartílago/crecimiento & desarrollo , Condrocitos/citología , Osteoartritis/metabolismo , Receptores de Activinas Tipo I/metabolismo , Animales , Proteína Quinasa CDC2/metabolismo , Cartílago/citología , Proliferación Celular , Condrocitos/metabolismo , Ciclina B/metabolismo , Mitosis , Proteínas Serina-Treonina Quinasas , Ratas , Ratas Wistar , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismoRESUMEN
PURPOSE: To investigate the expression of specific receptors, signal transducers and the effect of transforming growth factor-beta (TGF-beta) on retinal pigment epithelium (RPE) migration and proliferation. METHODS: Human RPE cell line D407 was used in all experiments. The effect of TGF-beta on migration and proliferation were studied using a wound healing model and [3H]-thymidine incorporation, respectively. The expression of RNA related to the TGF-beta superfamily receptors and SMAD1-4 were assayed by reverse transcriptase-polymerase chain reaction (RT-CPR). The effects of TGF-beta on the intracellular position of SMAD were studied by immunoperoxidase and immunofluorescence. RESULTS: Transforming growth factor-beta 4 nm and activin A 0.36 nm stimulated RPE migration. There was no effect on proliferation. RNA for TGF-beta receptors types 1 and 2, and SMAD1-4 were detected in RPE culture. Transforming growth factor-beta signal transducer SMAD2 but not SMAD1 moved from the cytoplasm to the nucleus after TGF-beta stimulation. CONCLUSION: Transforming growth factor-beta can regulate RPE cell migration through specific signal transduction pathways.
Asunto(s)
Activinas/farmacología , Movimiento Celular/efectos de los fármacos , Subunidades beta de Inhibinas/farmacología , Epitelio Pigmentado Ocular/citología , Factor de Crecimiento Transformador beta/farmacología , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo I/metabolismo , División Celular/efectos de los fármacos , Línea Celular , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Técnicas para Inmunoenzimas , Epitelio Pigmentado Ocular/metabolismo , Proteínas Serina-Treonina Quinasas , ARN Mensajero/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Smad , Proteína Smad1 , Proteína Smad2 , Proteína smad3 , Proteína Smad4 , Transactivadores/genética , Transactivadores/metabolismo , Cicatrización de Heridas/fisiologíaRESUMEN
PURPOSE: assess the latent and active TGFb1 localization in the lung, whether or not radiation induces latent TGFbeta1 activation, and the distribution of collagen fibers in the irradiated lung. METHODS: Thirty two C57BL mice were randomly assigned in two groups: GI (non irradiated animals) and GII (irradiated animals). The mice from GII received a single whole - body radiation dose of 7Gy, using a 60Co source at a dose rate of 0.97 Gy/min. They were sacrificed by cervical dislocation at 1, 14, 30 and 90 days after radiation. RESULTS: The irradiated lungs showed: 1) vascular congestion and thickness of the alveolar septa 30 days and more intense 90 days after irradiation; 2) significant increase of collagen deposition in all time periods after irradiation; 3) weak latent TGFbeta1 activation 1 day and strong activation 14 days after irradiation in the bronchi and alveoli. Our results suggest that some bronchial and alveolar cells may have a role in the complex process of radiation-induced lung fibrosis acting as cellular sources of active TGFbeta.