RESUMEN

Polypyrimidine tract-binding protein 1 (PTBP1) involving in almost all steps of mRNA regulation including alternative splicing metabolism during tumorigenesis due to its RNA-binding activity. Initially, we found that high expressed PTBP1 and poor prognosis was interrelated in colorectal cancer (CRC) patients with stages II and III CRC, which widely different in prognosis and treatment, by immunohistochemistry. PTBP1 was also upregulated in colon cancer cell lines. In our study, knockdown of PTBP1 by siRNA transfection decreased cell proliferation and invasion in vitro. Denovirus shRNA knockdown of PTBP1 inhibited colorectal cancer growth in vivo. Furthermore, PTBP1 regulates alternative splicing of many target genes involving in tumorgenesis in colon cancer cells. We confirmed that the splicing of cortactin exon 11 which was only contained in cortactin isoform-a, as a PTBP1 target. Knockdown of PTBP1 decreased the expression of cortactin isoform-a by exclusion of exon 11. Also the mRNA levels of PTBP1 and cortactin isoform-a were cooperatively expressed in colorectal cancer tissues. Knocking down cortactin isoform-a significantly decreased cell migration and invasion in colorectal cancer cells. Overexpression of cortactin isoform-a could rescue PTBP1-knockdown effect of cell motility. In summary the study revealed that PTBP1 facilitates colorectal cancer migration and invasion activities by inclusion of cortactin exon 11.

Asunto(s)

Empalme Alternativo , Neoplasias del Colon/genética , Neoplasias Colorrectales/genética , Cortactina/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Carcinogénesis , Procesos de Crecimiento Celular , Movimiento Celular , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/patología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Cortactina/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Ribonucleoproteínas Nucleares Heterogéneas/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Estadificación de Neoplasias , Proteína de Unión al Tracto de Polipirimidina/genética , Pronóstico , ARN Interferente Pequeño/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto Joven