Down-Regulation of Gli Transcription Factor Leads to the Inhibition of Migration and Invasion of Ovarian Cancer Cells via Integrin β4-Mediated FAK Signaling

作者：Qi Chen, Rong Xu, Chunyan Zeng, Quqin Lu, Dengliang Huang, Chao Shi, Weilong Zhang, Libin Deng, Runwei Yan, Hai Rao, Guolan Gao, Shiwen Luo · 发表于：PLoS ONE · 年份：2014 · DOI：10.1371/journal.pone.0088386 · 被引用次数：78 · 研究领域：Hedgehog Signaling Pathway Studies、TGF-β signaling in diseases、Glioma Diagnosis and Treatment

BACKGROUND: Recent evidence suggests that aberrant activation of Hedgehog (Hh) signaling by Gli transcription factors is characteristic of a variety of aggressive human carcinomas including ovarian cancer. Therefore, chemotherapeutic agents that inhibit activation of Gli transcription factors have emerged as promising novel therapeutic drugs for ovarian cancer. RESULTS: In this study, we show that activation of Hh signaling promoted cellular migration and invasion, whereas blockade of Hh signaling with GANT61 suppressed cellular migration and invasion in ovarian cancer cells. After treatment with GANT61, cDNA microarray analyses revealed changes in many genes such as Integrin β4 subunit (ITGB4), focal adhesion kinase (FAK), etc. Furthermore, ITGB4 expression was up-regulated by Sonic Hedgehog (Shh) ligand and down-regulated by Hh signaling inhibitor. The Shh-mediated ovarian cell migration and invasion was blocked by neutralizing antibodies to ITGB4. In addition, phosphorylations of FAK were increased by Shh and decreased by Hh signaling inhibitor. Inhibition of Gli1 expression using siRNA mimicked the effects of GANT61 treatment, supporting the specificity of GANT61. Further investigations showed that activation of FAK was required for Shh-mediated cell migration and invasion. Finally, we found that down-regulation of Gli reduced the expression of ITGB4 and the phosphorylated FAK, resulting in the inhibition of tumor growth in vivo. CONCLUSIONS: The Hh signaling pathway indu...