RESUMEN
Fibroblasts in the tumor microenvironment are a key determinant in cancer progression and may be a promising target for cancer therapy. Insulin-like growth factor binding protein 7 (IGFBP7) is known as a tumor suppressor in colorectal cancer (CRC). The present study investigated the inductive mechanism of IGFBP7 expression in fibroblasts by supernatant from the CRC cell line, SW620. The results showed that the expression of IGFBP7 was up-regulated in the fibroblasts when treated with SW620 supernatant and exogenous TGF-ß1. The IGFBP7 induced by SW620 supernatant or TGF-ß1 was partially inhibited by the TGF-ß1 specific antibody AF and TGF-ß1 receptor antagonist SB431542. The Wnt signaling-targeted genes, c-Myc, CCND1 and the proteins Dvl2/3, were all up-regulated in fibroblasts expressing high levels of IGFBP7, and the up-regulation could be inhibited both by the Wnt signaling antagonist Dickkopf-1 (DKK1) and by the TGF-ß1 receptor antagonist SB431542. In conclusion, CRC cells promote the high expression of IGFBP7 in fibroblasts, most likely through the co-regulation of TGF-ß and Wnt signaling in a Smad2/3-Dvl2/3 dependent manner. Taken together, these data suggest that the fibroblasts could be a novel therapeutic target in tumor therapy.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias Colorrectales/metabolismo , Fibroblastos/metabolismo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Fosfoproteínas/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Medios de Cultivo Condicionados/farmacología , Proteínas Dishevelled , Fibroblastos/efectos de los fármacos , Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/farmacología , Regulación hacia Arriba , Vía de Señalización WntRESUMEN
TGF-ß signaling pathway plays a central role in the signaling networks that control the growth, differentiation of the cell, and the initiation of fibrosis and cancer. Wnt signaling pathway is critical for the embryonic development and the invasion and migration of cancer cells. TGF-ß signaling and Wnt signaling, both of which play an important role in regulating embryonic development, fibrotic disease and tumor progression, have a close relationship. Researches find several typical cross points between these two signaling systems, such as Smad, Axin, Dvl and ß-catenin. In this review, we focus on the crosstalk between TGF-ß signaling and Wnt signaling through these typical factors, intending to better understand the process of fibrosis and tumor progression.