Publication: Función de C3G en la regulación del crecimiento y progresión tumoral en hepatocarcinoma. Implicación en la ruta de señalización de HGF/Met
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2021-02-15
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Universidad Complutense de Madrid
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Abstract
“Introducción” El hepatocarcinoma (HCC) es el cáncer de hígado más común, y el cuarto en mortalidad dentro del conjunto de muertes relacionadas con cáncer. El HCC se caracteriza por un patrón muy heterogéneo entre pacientes que complica su clasificación de cara al pronóstico y/o tratamiento. El HCC se inicia en hígados predispuestos por diversos determinantes como la inflamación crónica, cirrosis, virus de la hepatitis B o C, consumo de alcohol y enfermedades no ligadas al alcohol, que frecuentemente dan lugar a la adquisición de una primera mutación en el promotor de TERT, y luego, se acumulan una serie de alteraciones genéticas progresando desde HCC temprano a avanzado, dando lugar a metástasis de pulmón, prevalentemente. La EMT (transición epitelio-mesénquima) permite a las células epiteliales adquirir propiedades pro-migratorias y pro-invasivas, que son necesarias para conducir a las células de carcinoma hacia un fenotipo metastásico. Como en otros cánceres, en el HCC, el microambiente tumoral también es relevante para su desarrollo, el cual, está formado por miofibroblastos, fibroblastos asociados al cáncer, células hepáticas estrelladas, células del sistema inmunitario y otros tipos de células que secretan varios factores y citoquinas. Esto permite establecer una comunicación bidireccional entre el estroma y las células tumorales, que contribuye al crecimiento tumoral y/o a la generación de metástasis. C3G es un factor que activa el intercambio de nucleótidos de guanina (GEF) de las GTPasas monoméricas de la superfamilia Ras, principalmente Rap1 y R-Ras. Sin embargo, puede actuar de forma dependiente o independiente de la activación de Rap1, gracias a la presencia en su estructura de un dominio rico en prolinas que puede unirse a dominios SH3 de otras proteínas (Crk, Src, p130Cas…) y un dominio de unión de E-cadherina, además de su dominio catalítico GEF. C3G es esencial para el desarrollo embrionario y está implicado en muchas funciones biológicas como motilidad, adhesión, tráfico de vesículas, muerte celular y supervivencia, diferenciación y función plaquetaria. Más recientemente, se han descubierto otras funciones de C3G relacionadas con su localización nuclear. La función de C3G en cáncer es controvertida y puede actuar tanto como supresor tumoral (por ej. en cáncer de mama y carcinoma escamoso de cérvix), como promotor tumoral (por ej. en leucemia crónica mieloide y cáncer pulmonar de células no pequeñas) o ambos (por ej. en cáncer colorrectal). Sin embargo, no hay datos disponibles en la literatura sobre el papel de C3G en HCC. Sólo hay algunos datos sobre la función potencial de Rap1 y Rap2, pero son controvertidos...
“Introduction “ Hepatocarcinoma (HCC) is the most common liver cancer and the fourth in cancer-related mortality worldwide. HCC is characterized by a very heterogeneous pattern between patients that complicates its classification for prognosis and/or therapy purposes. HCC is initiated in livers predisposed by diverse determinants such as chronic inflammation, cirrhosis, hepatitis B or C virus, alcohol intake and non-alcoholic liver diseases, which frequently acquire a first mutation in the TERT promoter, and then, accumulate a series of genetic alterations progressing from early to advanced HCC, leading to lung metastasis, prevalently. EMT (epithelial-mesenchymal transition) enables epithelial cells to acquire pro-migratory and pro-invasive properties, which is necessary for driving carcinoma cells towards a metastatic phenotype. As in other cancers, in HCC, the tumor microenvironment is also relevant for its development, which is comprised by myofibroblast, cancer-associated fibroblasts, hepatic stellate cells, immune system cells and other cell types that secrete several factors and cytokines. Thus, establishing a bidirectional communication between stroma and tumor cells that contributes to tumor growth and/or metastasis generation. C3G is a guanine nucleotide exchange factor (GEF) for some members of the Ras superfamily of small GTPases, mainly Rap1 and R-Ras. However, it can act either dependently or independently of Rap1 activation, thanks to the presence in its structure of a proline rich domain that can bind to the SH3 domain of other proteins (Crk, Src, p130Cas…) and an E-cadherin-binding domain, in addition to its GEF catalytic domain. C3G is essential for embryonic development and is implicated in many biological functions, such as cell motility, adhesion, vesicle trafficking, cell death and survival, differentiation and platelet function. More recently, other functions of C3G related to its nuclear localization has been discovered. The function of C3G in cancer is controversial as it can act as either a tumor suppressor (e.g. in breast cancer and cervical squamous carcinoma) or a tumor promoter (e.g. in chronic myeloid leukemia and non-small cell lung cancer) or both (e.g. in colorectal cancer). However, there are no data available in the literature about the role of C3G in HCC. There are just a few data about a potential function of Rap1 and Rap2, but they are controversial...
“Introduction “ Hepatocarcinoma (HCC) is the most common liver cancer and the fourth in cancer-related mortality worldwide. HCC is characterized by a very heterogeneous pattern between patients that complicates its classification for prognosis and/or therapy purposes. HCC is initiated in livers predisposed by diverse determinants such as chronic inflammation, cirrhosis, hepatitis B or C virus, alcohol intake and non-alcoholic liver diseases, which frequently acquire a first mutation in the TERT promoter, and then, accumulate a series of genetic alterations progressing from early to advanced HCC, leading to lung metastasis, prevalently. EMT (epithelial-mesenchymal transition) enables epithelial cells to acquire pro-migratory and pro-invasive properties, which is necessary for driving carcinoma cells towards a metastatic phenotype. As in other cancers, in HCC, the tumor microenvironment is also relevant for its development, which is comprised by myofibroblast, cancer-associated fibroblasts, hepatic stellate cells, immune system cells and other cell types that secrete several factors and cytokines. Thus, establishing a bidirectional communication between stroma and tumor cells that contributes to tumor growth and/or metastasis generation. C3G is a guanine nucleotide exchange factor (GEF) for some members of the Ras superfamily of small GTPases, mainly Rap1 and R-Ras. However, it can act either dependently or independently of Rap1 activation, thanks to the presence in its structure of a proline rich domain that can bind to the SH3 domain of other proteins (Crk, Src, p130Cas…) and an E-cadherin-binding domain, in addition to its GEF catalytic domain. C3G is essential for embryonic development and is implicated in many biological functions, such as cell motility, adhesion, vesicle trafficking, cell death and survival, differentiation and platelet function. More recently, other functions of C3G related to its nuclear localization has been discovered. The function of C3G in cancer is controversial as it can act as either a tumor suppressor (e.g. in breast cancer and cervical squamous carcinoma) or a tumor promoter (e.g. in chronic myeloid leukemia and non-small cell lung cancer) or both (e.g. in colorectal cancer). However, there are no data available in the literature about the role of C3G in HCC. There are just a few data about a potential function of Rap1 and Rap2, but they are controversial...
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Tesis inédita de la Universidad Complutense de Madrid. Facultad de Farmacia, leída el 08-05-2020