RESUMEN
Malignant pleural mesothelioma (MPM) is an aggressive type of cancer of the thoracic cavity commonly associated with asbestos exposure and a high mortality rate. There is a need for new molecular targets for the development of more effective therapies for MPM. Using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and an RNA interference-based screening, we examined the SORORIN gene as potential therapeutic targets for MPM in addition to the PLK1 gene, which is known for kinase of SORORIN. Following in vitro investigation of the effects of target silencing on MPM cells, cell cycle analyses were performed. SORORIN expression was analyzed immunohistochemically using a total of 53 MPM samples on tissue microarray. SORORIN was found to be overexpressed in the majority of clinical MPM samples and human MPM cell lines as determined by qRT-PCR. Gene suppression of each SORORIN and PLK1 led to growth inhibition in MPM cell lines. Knockdown of SORORIN showed an increased number of G2M-phase population and a larger nuclear size, suggesting mitotic arrest. High expression of SORORIN (SORORIN-H) was found in 50.9% of all the MPM cases, and there is a tendency towards poorer prognosis for the SORORIN-H group but the difference is not significant. Suppression of SORORIN with PLK1 inhibitor BI 6727 showed a combinational growth suppressive effect on MPM cell growth. Given high-dose PLK1 inhibitor induced drug-related adverse effects in several clinical trials, our results suggest inhibition SORORIN-PLK1 axis may hold promise for the treatment of MPMs.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas de Ciclo Celular/antagonistas & inhibidores , Neoplasias Pulmonares/patología , Mesotelioma/patología , Neoplasias Pleurales/patología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Mesotelioma Maligno , Persona de Mediana Edad , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Pteridinas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Quinasa Tipo Polo 1RESUMEN
Malignant pleural mesothelioma (MPM) is a rare and aggressive form of cancer commonly associated with asbestos exposure that stems from the thoracic mesothelium with high mortality rate. Currently, treatment options for MPM are limited, and new molecular targets for treatments are urgently needed. Using quantitative reverse transcription-polymerase chain reaction (RT-PCR) and an RNA interference-based screening, we screened two kinesin family members as potential therapeutic targets for MPM. Following in vitro investigation of the target silencing effects on MPM cells, a total of 53 MPMs were analyzed immunohistochemically with tissue microarray. KIF11 and KIF23 transcripts were found to be overexpressed in the majority of clinical MPM samples as well as human MPM cell lines as determined by quantitative RT-PCR. Gene knockdown in MPM cell lines identified growth inhibition following knockdown of KIF11 and KIF23. High expression of KIF11 (KIF11-H) and KIF23 (KIF23-H) were found in 43.4 and 50.9% of all the MPM cases, respectively. Patients who received curative resection with tumors displaying KIF23-H showed shorter overall survival (P=0.0194). These results provide that inhibition of KIF11 and KIF23 may hold promise for treatment of MPMs, raising the possibility that kinesin-based drug targets may be developed in the future.
Asunto(s)
Cinesinas/genética , Mesotelioma/genética , Mesotelioma/terapia , Proteínas Asociadas a Microtúbulos/genética , Neoplasias Pleurales/genética , Neoplasias Pleurales/terapia , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Cinesinas/biosíntesis , Masculino , Mesotelioma/metabolismo , Mesotelioma/patología , Proteínas Asociadas a Microtúbulos/biosíntesis , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias Pleurales/metabolismo , Neoplasias Pleurales/patología , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Matrices Tisulares , TransfecciónRESUMEN
No abstract available.
Asunto(s)
Tumores de Células Gigantes , Células Gigantes , Articulación de la Rodilla , RodillaRESUMEN
No abstract available.
RESUMEN
No abstract available.
Asunto(s)
Conejos , Período de Latencia Psicosexual , Osteogénesis por DistracciónRESUMEN
No abstract available.