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Previous issue date: 2018-04-27 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Esophageal cancer, in general, is diagnosed at an advanced stage, which leads to
impairment in the therapies employed, resulting in a high mortality rate. It is classified into two subtypes: adenocarcinoma and squamous cell carcinoma; both differ in histology, etiology and epidemiology. Purinergic signaling uses nucleotides and nucleosides in the extracellular medium as signaling molecules, and has been linked to different types of carcinomas. These molecules bind to G-protein coupled adenosine receptors, characterized as P1 (A1, A2A, A2B and A3), to P2X ionotropic receptors (P2X1-P2X7), and to P2Y receptors (P2Y 1, 2, 4, 6, 11, 12, 13 14), coupled to G protein. Given the evidence described in the literature and the lack of data correlating purinergic signaling with esophageal cancer, we analyzed the role of P2Y2 (P2Y2R) and P2Y12 (P2Y12R) receptors in the processes of proliferation, colony formation capacity, migration, adhesion, enzymatic activity of the ectonucleotidases and signaling pathways after the nucleotide stimulation. For this, we used the Kyse- 30 and Kyse-450 cells, representative of squamous cell carcinoma, and the OE-33
line, representative of adenocarcinoma. Also, we verified the expression of P2Y2R in
biopsies of patients with squamous cell carcinoma and adenocarcinoma, compared
to non-neoplastic tissues. We observed that the biopsy specimens express the P2Y2
receptor, but at different labeling intensities. The cell lines expressing P2Y2 and
P2Y12R, have different responses to the stimulus with the nucleotides ADP, ATP and
UTP, but the blockade of these receptors leads to a decrease in proliferation,
polyclonal population formation, adhesion and migration. Regarding the pathways
related to the action of P2Y2R, we verified the activation of ERK1 / 2 and Akt at
different times after the stimulation with ATP and UTP. The data presented in this
study demonstrate that the modulation of purinergic receptors P2Y2 and P2Y12 may
become a promising tool for achieving efficacy in the treatment of esophageal cancer. / O c?ncer de es?fago, em geral, ? diagnosticado em est?gio avan?ado, o que leva a um preju?zo nas terapias empregadas, resultando em uma alta taxa de mortalidade. ? dividido em dois subtipos: adenocarcinoma e carcinoma de c?lulas escamosas; os dois subtipos diferem quanto a histologia, etiologia e epidemiologia. A sinaliza??o purin?rgica utiliza nucleot?deos e nucleos?deos no meio extracelular como mol?culas sinalizadoras e j? foi relacionada com diferentes tipos de carcinomas. Essas mol?culas ligam-se a receptores para adenosina acoplados a prote?na G, caracterizados como P1 (A1, A2A, A2B e A3), a receptores ionotr?picos P2X (P2X1- P2X7), e ainda a receptores P2Y (P2Y1, 2, 4, 6, 11, 12,13 14), acoplados a prote?na G. Diante
das evid?ncias descritas na literatura e a falta de dados correlacionando a sinaliza??o purin?rgica com c?ncer de es?fago, analisamos o papel dos receptores P2Y2 (P2Y2R) e P2Y12 (P2Y12R) nos processos de prolifera??o, capacidade de forma??o de col?nias, migra??o, ades?o e atividade enzim?tica das
ectonucleotidases e vias de sinaliza??o envolvidas, ap?s o est?mulo com nucleot?deos. Para isso, utilizamos as c?lulas Kyse-30 e Kyse-450, representativas de carcinoma de c?lulas escamosas, e a linhagem OE-33, representativa de adenocarcinoma. Tamb?m, verificamos a express?o do P2Y2R em bi?psias de
pacientes com carcinoma de c?lulas escamosas e adenocarcinoma, comparadas com tecidos n?o neopl?sicos. Observamos que as amostras de bi?psia expressam o receptor P2Y2, por?m em diferentes intensidades de marca??o. As linhagens celulares expressam P2Y2 e P2Y12R, possuem diferentes respostas frente ao est?mulo com os nucleot?deos ADP, ATP e UTP, por?m o bloqueio desses receptores leva ?
diminui??o da prolifera??o, forma??o de popula??o policlonal, ades?o e migra??o. Quanto ?s vias relacionadas ? a??o do P2Y2R, verificamos a ativa??o de ERK1/2 e Akt em diferentes tempos ap?s o est?mulo com ATP e UTP. Os dados apresentados neste estudo demonstram que a modula??o de receptores purin?rgicos P2Y2 e P2Y12, pode tornar-se uma ferramenta promissora para alcan?ar efic?cia no
tratamento do c?ncer de es?fago.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/8275 |
| Date | 27 April 2018 |
| Creators | Zaparte, Aline |
| Contributors | Morrone, Fernanda Bueno |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Medicina e Ci?ncias da Sa?de, PUCRS, Brasil, Escola de Medicina |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 7620745074616285884, 500, 500, 500, 600, -224747486637135387, -969369452308786627, 2075167498588264571 |
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