{"id":110204,"date":"2018-03-11T10:36:09","date_gmt":"2018-03-11T10:36:09","guid":{"rendered":"https:\/\/www.deberes.net\/tesis\/sin-categoria\/papel-de-dusp1-en-progresion-tumoral-y-en-respuesta-a-cddp-en-cancer-no-microca%c2%adtico-de-pulmon\/"},"modified":"2018-03-11T10:36:09","modified_gmt":"2018-03-11T10:36:09","slug":"papel-de-dusp1-en-progresion-tumoral-y-en-respuesta-a-cddp-en-cancer-no-microca%c2%adtico-de-pulmon","status":"publish","type":"post","link":"https:\/\/www.deberes.net\/tesis\/sin-categoria\/papel-de-dusp1-en-progresion-tumoral-y-en-respuesta-a-cddp-en-cancer-no-microca%c2%adtico-de-pulmon\/","title":{"rendered":"\u00abpapel de dusp1 en progresi\u00f3n tumoral y en respuesta a cddp en c\u00e1ncer no microc\u00edtico de pulm\u00f3n\u00bb."},"content":{"rendered":"<h2>Tesis doctoral de <strong> Veronica Moncho Amor <\/strong><\/h2>\n<p>Dusp1 es una fosfatasa que regula la actividad de las mapk, jnk y p38, que adem\u00e1s tiene un papel significativo en la biolog\u00eda tumoral y en la resistencia al cisplatino (cddp). En este trabajo se estudia la funci\u00f3n de dusp1 en c\u00e1ncer no microc\u00edtico de pulm\u00f3n (cnmp). Para ello se realiz\u00f3 un an\u00e1lisis diferencial de la expresi\u00f3n g\u00e9nica global entre c\u00e9lulas de cnmp parentales (h460v) y c\u00e9lulas con expresi\u00f3n de dusp1 inhibida (h460cri). En este estudio se observ\u00f3 que la inhibici\u00f3n en la expresi\u00f3n de dusp1 induce cambios en las rutas biol\u00f3gicas involucradas en angiog\u00e9nesis, actividad map quinasa, se\u00f1alizaci\u00f3n c\u00e9lula-c\u00e9lula, la actividad del factores de crecimiento y receptores tirosina-quinasa. Estas diferencias observadas en expresi\u00f3n g\u00e9nica se complementaron con ensayos funcionales para estudiar la implicaci\u00f3n de dusp1 en angiog\u00e9nesis y met\u00e1stasis. Se observ\u00f3 que en c\u00e9lulas h460, la inhibici\u00f3n de la expresi\u00f3n dusp1 disminuye la capacidad migratoria e invasiva, el crecimiento de tumores en ratones inmunodeprimidos y la met\u00e1stasis inducida por estas c\u00e9lulas. Tambi\u00e9n se observ\u00f3 que la inhibici\u00f3n de dusp1 reduce el potencial angiog\u00e9nico in vivo, dato que correlaciona con una disminuci\u00f3n de la producci\u00f3n de vegfc. A ra\u00edz de estos resultados, se realiz\u00f3 una aproximaci\u00f3n translacional con muestras de biopsias de tumores de pacientes con cnmp, observ\u00e1ndose una estrecha correlaci\u00f3n entre la expresi\u00f3n de vegfc y dusp1 en las zonas de mayor vascularizaci\u00f3n. la expresi\u00f3n de dusp1 parece estar relacionada con la resistencia encontrada frecuentemente en pacientes de cnmp al cddp, quimioter\u00e1pico de uso habitual en este tumor. Por tanto, se quiso profundizar en el conocimiento del papel de dusp1 en respuesta al cddp en c\u00e9lulas de cnmp. Para ello, se trataron las c\u00e9lulas h460v y h460cri con cddp a diferentes tiempos y se estudiaron los cambios en la expresi\u00f3n g\u00e9nica mediante el uso de microarrays de expresi\u00f3n. Los resultados obtenidos indican que las c\u00e9lulas h460cri son m\u00e1s sensibles al cddp, con un aumento en el porcentaje en c\u00e9lulas apopt\u00f3ticas tras su tratamiento con este agente. En ambas l\u00edneas celulares la apoptosis est\u00e1 mediada por la actividad de p38, aunque en c\u00e9lulas h460v la activaci\u00f3n de la apoptosis es v\u00eda p38-atf2, mientras que en c\u00e9lulas h460cri parece ser independiente de atf2 como conclusi\u00f3n los resultados indican que dusp1 juega un papel importante en la progresi\u00f3n tumoral en cnmp, probablemente debido a su participaci\u00f3n en los procesos de angiog\u00e9nesis y met\u00e1stasis; adem\u00e1s dusp1 parece estar implicada en la aparici\u00f3n de resistencia al agente cddp a trav\u00e9s de una sutil regulaci\u00f3n de los procesos apoptot\u00f3ticos mediados por la ruta p38.  dusp1 is a phosphatase that regulates the activity of the mapk, jnk and p38, with an increasingly recognized implication in tumor biology and resistance to cisplatin (cddp). To understand more about the role of dusp1 in non-small cell lung cancer (nsclc), gene expression analysis was performed comparing parental versus dusp1- defficient h460 nsclc cancer cells. Results showed that inhibition in dusp1 expression induces changes in specific biological pathways including angiogenesis, map-kinase phosphatase activity, cell-cell signalling, growth factor and tyrosine-kinase receptor activity. Then, complementary functional assays were performed focussed on the implication of dusp1 in angiogenesis and metastasis. In h460 cells, inhibition of dusp1 expression resulted in a diminished capacity to migrate, invade, generate tumors in nude mice and to metastasize. Furthermore, h460cri cells have a reduced angiogenic potential in vivo, which correlates with a decrease in vegfc expression. Finally, we studied the relevance of these findings in human nsclc specimens. A significant correlation was found between vegfc and dusp1 expression that localize next to vascular structures. cddp-based chemotherapy is the first option treatment in nsclc and the expression of dusp1 seems to be related to cddp resistance in those patients. To gain insight into the cellular signaling pathways involving dusp1 actions and the response to cddp in nsclc; h460v and h460cri cells were treated during different times with cddp and the gene expression analysis was studied using microarrays. Results indicated the h460cri cells were more sensitive to cddp and that the percentage of apoptotic cells increased after treatment. In both cell lines the apoptosis is mediated by p38 activity, although in h460v cells the activation of apoptosis occurs by p38-atf2 pathway, while in h460cri cells seems to be independent of atf2. overall, this work provides evidence on the role of dusp1 in tumor progression in nsclc, which is probably related to its participation in angiogenesis and metastasis; moreover dusp1 seems to be involved in cddp resistance through subtle changes in apoptotic processes regulation mediated by p38 signalling pathway.<\/p>\n<p>&nbsp;<\/p>\n<h3>Datos acad\u00e9micos de la tesis doctoral \u00ab<strong>\u00abpapel de dusp1 en progresi\u00f3n tumoral y en respuesta a cddp en c\u00e1ncer no microc\u00edtico de pulm\u00f3n\u00bb.<\/strong>\u00ab<\/h3>\n<ul>\n<li><strong>T\u00edtulo de la tesis:<\/strong>\u00a0 \u00abpapel de dusp1 en progresi\u00f3n tumoral y en respuesta a cddp en c\u00e1ncer no microc\u00edtico de pulm\u00f3n\u00bb. <\/li>\n<li><strong>Autor:<\/strong>\u00a0 Veronica Moncho Amor <\/li>\n<li><strong>Universidad:<\/strong>\u00a0 Aut\u00f3noma de Madrid<\/li>\n<li><strong>Fecha de lectura de la tesis:<\/strong>\u00a0 14\/07\/2011<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<h3>Direcci\u00f3n y tribunal<\/h3>\n<ul>\n<li><strong>Director de la tesis<\/strong>\n<ul>\n<li> <\/li>\n<\/ul>\n<\/li>\n<li><strong>Tribunal<\/strong>\n<ul>\n<li>Presidente del tribunal: amparo Cano garcia <\/li>\n<li>montserrat S\u00e1nchez c\u00e9spedes (vocal)<\/li>\n<li>cristobal Belda iniesta (vocal)<\/li>\n<li>Rafael Pulido murillo (vocal)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Tesis doctoral de Veronica Moncho Amor Dusp1 es una fosfatasa que regula la actividad de las mapk, jnk y p38, 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