Negrín, Lara M. (2015) Estudio de potenciales marcadores moleculares predictivos de radiosensibilidad en cáncer de piel tipo melanoma. / Study of potential predictive molecular markers of radiosensitivity in melanoma skin cancer. Maestría en Física Médica, Universidad Nacional de Cuyo, Instituto Balseiro.
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Resumen en español
La radioterapia es un componente esencial en el tratamiento contra el cáncer, el 50% de los pacientes diagnosticados con dicha enfermedad reciben esta terapia al menos una vez durante su tratamiento. La radiosensibilidad individual es un factor determinante en la eficacia de esta modalidad radioterapéutica siendo responsable de las reacciones adversas y complicaciones que pudieran suceder. El desarrollo de ensayos específicos con potencial diagnóstico que permitan la identificación de la radiosensibilidad de los pacientes permitirá identificar la estrategia terapéutica más apropiada y específica a ser aplicada para cada paciente, contribuyendo a personalizar la terapia radiante. El objetivo de este trabajo fue estudiar de manera preliminar la respuesta a las radiaciones ionizantes a nivel de la regulación génica relacionada con la radiosensibilidad intrínseca de células de melanoma provenientes de la misma línea celular, A-375 que muestran distinto grado de agresividad, PCDNA3, A7 y G10. Las células A7 son más diferenciadas, presentando mayor grado de polaridad y melanogénesis a diferencia de las células control PCDNA3 que presenta el mismo fenotipo que las células A-375. Por otro lado, las células G10 son apolares e invasivas con respecto a las A7 y al control PCDNA3. El fin último de la serie de trabajos iniciados en esta tesis radica en la posibilidad de detectar potenciales biomarcadores predictivos del comportamiento celular frente a las radiaciones ionizantes. Se evaluó la fracción de sobrevida de las células de melanoma tratadas con dosis de 1Gy, 2Gy, 3Gy y 5Gy mediante un ensayo clonogenicidad y se estudió la inducción de rupturas de doble cadena de ADN mediante la técnica de inmunocitofluorescencia y cuantificación de γ-H2AX 30 min post-irradiación en células tratadas con dosis de 2 Gy de radiación gamma. Las células de melanoma G10 presentaron mayor resistencia a los efectos citotóxicos de las radiaciones ionizantes que las células PCDNA3 y A7. Estás últimas exhibieron un comportamiento similar de radiosensibilidad. En cuanto al análisis de las rupturas de doble cadena de ADN, se observó un aumento en el número de focos de la histona γ-H2AX en las tres líneas celulares tratadas con 2 Gy de radiación gamma, con mayor inducción de las células A7 y menor inducción en las células G10. La regulación génica de los procesos implicados en la respuesta a los efectos biológicos de las radiaciones ionizantes se estudió mediante un análisis bioinformático de datos de microarrays obtenidos previamente en el laboratorio. Se comparó la expresión de los genes que participan en los procesos de señalización y reparación de DSB, regulación del ciclo celular, apoptosis y señalización de p53, procesos claves para la viabilidad celular en términos de su capacidad reproductiva. El análisis de expresión indicó la presencia de 22 genes sub-expresados en la línea G10 que podrían estar implicados en la radiorresistencia que presenta esta línea celular. Dada la importancia de la señalización y reparación de DSB en la respuesta celular radioinducida, y considerando la evidencia bibliográfica encontrada que postula al gen MRE11 como un posible biomarcador de radiosensibilidad, se seleccionó este gen como candidato predictivo a partir del conjunto de genes sub-expresados en G10 para validar su expresión mediante un análisis de PCR real time. El gen MRE11 es un actor clave en la respuesta al daño del ADN. En este trabajo de tesis se encontró que dicho gen se sub-expresa en la línea G10. También se pudo inferir que la sub-expresión de este gen no es alterada por efecto de las radiaciones ionizantes pero que existe una correlación positiva entre la baja expresión del gen MRE11 y la radiorresistencia en las células de melanoma estudiadas en este trabajo. Estos resultados permiten disponer de una primera aproximación de la regulación génica de los procesos asociados a la modulación de la radiosensibilidad en células de melanoma, indicando un posible rol del gen MRE11 en la radiorresistencia característica de las células G10. Teniendo en cuenta su función e importancia en la señalización de las rupturas de doble cadena de ADN y la relación directa entre este proceso y los efectos biológicos de las radiaciones ionizantes, surgen de este trabajo premisas para continuar el estudio del gen MRE11 como potencial biomarcador de radiosensibilidad intrínseca.
Resumen en inglés
Radiation therapy is an essential component in cancer treatment; half of patients diagnosed with the disease receive this therapy at least once during treatment. Individual radiosensitivity is a determining factor in the effectiveness of this therapy, which may be responsible for complications and adverse reactions that may occur. The development of specific diagnostic tests that allow the identification of patients radiosensitivity will identify the most appropriate and specific therapeutic strategy to be applied to each patient, helping to personalize the radiation therapy. The objective of this work was to study gene regulation processes associated with modulation of the intrinsic radiosensitivity of melanoma cells derived from the A-375 cell line with different degrees of aggressiveness, PCDNA3, A7 and G10, in order to detect potential predictive biomarkers of cell behavior against ionizing radiation. A7 cells are more differentiated, showing a higher degree of polarity and melanogenesis than G10 cells and PCDNA3 control which express the same phenotype as A-375 cells. On the other hand, G10 cells are non polar and invasive as compared with A7 and PCDNA3 cells. Survival fraction of melanoma cells treated with a dose of 1 Gy, 2 Gy, 3Gy to 5 Gy, was evaluated by clonogenicity assay, determining the cellular radiosensitivity. Double-strand breaks (DSB) induced in DNA 30 min post-irradiation were studied in cells treated with 2 Gy of gamma radiation by immunocytofluorescence technique and γ-H2AX quantitation, G10 cells showed higher resistance to the cytotoxic effects of ionizing radiation than A7 and PCDNA3 cells. These two lines exhibited similar behavior of radiosensitivity. For DSB analysis, an increase in the number of γ-H2AX foci was observed in all three cell lines treated with 2 Gy of gamma radiation, with the most induction in A7 cells and the low induction in G10 cells. Gene regulation of the processes involved in the response to the biological effects of ionizing radiation was studied using a bioinformatic analysis of microarray data previously obtained in the laboratory. Expression of genes involved in DSB signaling and repair, cell cycle regulation, apoptosis and p53 signaling, which are essential for cell viability in terms of their reproductive activity was compared. Expression analysis showed 22 genes down-regulated in the G10 line which could be involved in its radioresistance. Given the importance of the DSB signaling and repair in the radiation-induced cellular response and considering bibliographic evidence that suggest MRE11 gene as a biomarker for radiosensintivity, this gene was selected from the down-regulated set in G10 line for evaluation as predictive candidate and its expression was validated by real time PCR analysis. The MRE11 gene is a key player in the response to DNA damage and it was found sub-expressed in the G10 line. The expression of this gene was not induced by ionizing radiation but a positive correlation between low expression of the MRE11 gene and radioresistance was found in the melanoma cells studied in this work. These results allowed a first approximation of gene regulation processes associated with modulation of radiosensitivity in melanoma cells, indicating a possible role of MRE11 gene in the radioresistance found in G10 cells. Given its role and importance in DSB signaling and its direct relationship between this process and the biological effects of ionizing radiation, the study of the MRE11 gene as a potential biomarker of intrinsic radiosensitivity should continue.
| Tipo de objeto: | Tesis (Maestría en Física Médica) |
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| Información Adicional: | Area temática: Radiobiología, Física Médica. |
| Palabras Clave: | Melanomas;Melanomas; Radiotherapy; Radioterapia; Neoplasms; Neoplasmas; Ionizing radiations; Radiaciones ionizantes; [Radiosensivity; Radiosensibilidad; Biomarker; Biomarcador] |
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| Materias: | Medicina > Oncología Medicina > Diagnóstico por imagen y medicina nuclear Medicina > Radioterapia Medicina |
| Divisiones: | Centro Atómico Constituyentes (CAC) |
| Código ID: | 517 |
| Depositado Por: | USUARIO INVÁLIDO |
| Depositado En: | 15 Mar 2016 11:25 |
| Última Modificación: | 15 Mar 2016 11:25 |
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