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Publication
Efeito de diferentes terapêuticas citotóxicas na expressão do CD133, Wnt/β-catenina no cancro do colo do útero
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Advisor(s)
Abstract(s)
O cancro do colo do útero é o quarto cancro mais comum a nível mundial. A quimioterapia e a radioterapia aplicada estão associadas a uma notável toxicidade e resistência. Postula-se que as células estaminais do cancro, assim como as vias associadas à sua manutenção, proliferação sejam responsáveis por estes mecanismos de resistência. O CD133 e a via Wnt/β-catenina estão associadas em alguns estudos a esta resistência.
Esta dissertação teve como objetivo avaliar a expressão da CD133, Wnt, β-catenina, LRP6, pLRP6, Naked1 e Axin1 após a exposição à radiação-X e o tratamento com a cisplatina tentando perceber se estas proteínas poderão ser utilizadas como alvo direto no tratamento, minimizando a toxicidade. Após determinar a concentração inibitória (IC50) média e a dose letal média (DL50) utilizaram-se concentrações e doses superiores, iguais e inferiores a estes valores, isto é, concentrações correspondentes à IC80, à IC50 e à IC20 e doses de 10 Gy, de DL50 e de 2 Gy. Avaliou-se a morte celular, o ciclo celular, a produção de espécies reativas de oxigénio, a glutationa reduzida e a expressão das proteínas (CD133, Wnt, β-catenina, LRP6, pLRP6, Naked1 e Axin1).
Após o tratamento com a cisplatina observou-se aumento da expressão da pLRP6 e diminuição da expressão da Naked1 e da Axin1 com o aumento da concentração do fármaco, o que poderá levar a localização nuclear da β-catenina e induzir a transcrição de genes responsáveis pela sobrevivência e pela proliferação das células tumorais. A exposição a diferentes doses de radioterapia permitiu-nos observar que o aumento da expressão da β-catenina está associada a uma menor morte celular e que a menor expressão da CD133 está associada a uma maior morte celular. Estes resultados sugerem que estas proteínas são importantes na resposta ao tratamento e que minimizar a toxicidade será possível em doentes com esta neoplasia.
Cervical cancer is the fourth most common cancer worldwide. Its incidence and mortality vary according to the country's development index being more common in developing countries. Conventional treatments (chemotherapy and radiotherapy) are associated with high toxicity and resistance. It is postulated that the cancer stem cells as well the pathways responsible for their maintenance and proliferation are involved in these resistance mechanisms. CD133 and the pathway Wnt/ β-catenin are associated with these resistances in some studies. The objective of these thesis was to analyse the expression of Wnt, β-catenin, LRP6, pLRP6, Naked1 and Axin1 after cisplatin and radiotherapy exposure in the attempt to understand, if these proteins could be used as therapy targets in this cancer type. After determining the mean inhibitory concentration (IC50) and the median lethal dose (LD50), concentrations and doses above and below these values were used, namely, concentrations corresponding to IC80, IC50 and IC20 and doses of 10 Gy, LD50 and 2 Gy. We analysed cell death, cell cycle, reactive oxygen species, reduced glutathione and the expression levels of CD133, Wnt, β-catenina, LRP6, pLRP6, Naked1 and Axin1. After the treatment with cisplatin, we observed an increase in pLRP6 and a decrease in Naked1 and Axin1 expression, which can lead to nuclear localization of β-catenin and transcription of target genes. After radiotherapy we observed that increased β-catenin expression could be associated with low cellular death. On the other hand, low CD133 expression could be associated with increased cell death. These results suggest that these proteins are important in response to treatment and that minimizing toxicity will be possible in patients with this neoplasia.
Cervical cancer is the fourth most common cancer worldwide. Its incidence and mortality vary according to the country's development index being more common in developing countries. Conventional treatments (chemotherapy and radiotherapy) are associated with high toxicity and resistance. It is postulated that the cancer stem cells as well the pathways responsible for their maintenance and proliferation are involved in these resistance mechanisms. CD133 and the pathway Wnt/ β-catenin are associated with these resistances in some studies. The objective of these thesis was to analyse the expression of Wnt, β-catenin, LRP6, pLRP6, Naked1 and Axin1 after cisplatin and radiotherapy exposure in the attempt to understand, if these proteins could be used as therapy targets in this cancer type. After determining the mean inhibitory concentration (IC50) and the median lethal dose (LD50), concentrations and doses above and below these values were used, namely, concentrations corresponding to IC80, IC50 and IC20 and doses of 10 Gy, LD50 and 2 Gy. We analysed cell death, cell cycle, reactive oxygen species, reduced glutathione and the expression levels of CD133, Wnt, β-catenina, LRP6, pLRP6, Naked1 and Axin1. After the treatment with cisplatin, we observed an increase in pLRP6 and a decrease in Naked1 and Axin1 expression, which can lead to nuclear localization of β-catenin and transcription of target genes. After radiotherapy we observed that increased β-catenin expression could be associated with low cellular death. On the other hand, low CD133 expression could be associated with increased cell death. These results suggest that these proteins are important in response to treatment and that minimizing toxicity will be possible in patients with this neoplasia.
Description
Keywords
Cancro do colo do útero Células estaminais do cancro Cisplatina Radioterapia CD133 Wnt/B- Catenina