The role of Jagged1 and KLF4 in Twist1-induced angiogenesis and tumorigenesis

• Main Authors: Hsiao-Fan Chen, 陳筱凡
• Other Authors: Kou-Juey Wu
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/16311103440253743355

博士 === 國立陽明大學 === 生化暨分子生物研究所 === 102 === Angiogenesis is crucial for the growth and persistence of primary solid tumors and their metastases. Twist1, an important regulator of epithelial-mesenchymal transition (EMT), was shown to mediate tumor invasion and metastasis. Recent evidences suggested that Twist1 expression induced tumor angiogenesis, but the mechanism is still unclear. Notch signaling was demonstrated to be an important player in vascular development and tumor angiogenesis. KLF4 (Krüppel-like factor 4) was initially identified as a factor for the generation of induced pluripotent Krüppel-like factor 4) stem (iPS) cells. KLF4 also plays an important role in the differentiation of endothelial cells. Recent studies indicated that the stem-like cells could transdifferentiate into vascular endothelial cells. Although Twist1 was known as a master regulator of mesoderm development, it is unknown whether Twist1 could involve in endothelial transdifferentiation of tumor-derived cells. Here we show that Twist1 overexpression appears endothelial phenotype and induces expression of endothelial specific markers through activation of Jagged1, a Notch ligand, in head and neck cancer cells. Furthermore, activation of KLF4 by Jagged1/Notch signaling is essential for the endothelial transdifferentiation and expression of endothelial and vascular markers induced by Twist1. Inhibition of either Jagged1 or KLF4 also decreased tumor metastasis, indicating the role of endothelial differentiation to support metastasis. Treatment of Twist1-overexpressing xenotransplanted tumor with a -secretase inhibitor (DAPT), used to block Notch signaling, in combination chemotherapy significantly inhibited the tumor growth. These results indicate that the Twist1-Jagged1/Notch-KLF4 axis is a crucial pathway for tumor-derived endothelial transdifferentiation and tumorigenesis, and provide a new therapeutic strategy against tumor-derived endothelial differentiation and angiogenesis.