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

Abstract

BackgroundRecent 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.ResultsIn 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.ConclusionsThe Hh signaling pathway induces cell migration and invasion through ITGB4-mediated activation of FAK in ovarian cancer. Our findings suggest that the diminishment of crosstalk between phosphorylated FAK and ITGB4 due to the down-regulation of Gli family transcription factors might play a pivotal role for inhibiting ovarian cancer progression.

Casticin inhibits the epithelial-mesenchymal transition in ovarian carcinoma via the hedgehog signaling pathway

“…Gli-1, a potent inducer of downstream target genes, is itself a transcriptional target of Hh signaling (36); however, Gli-1 induction prevents E-cadherin expression in kidney epithelium (37). Additionally, downregulation of Gli-1 induces the invasion and migration of ovarian cancer cells (38), and Gli-1 expression in advanced ovarian cancer may be associated with poor survival (39). It is reported that tumor progression requires a variety of phenotypical alterations that decrease intercellular adhesion, with EMT serving a key role (40).…”

Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism

“…6A). To further verify transcriptional activity of Gli2/Hh signaling, which may be potentially affected by phosphorylated SuFu, we performed a dual luciferase reporter assay in SKOV3 cells which is Hh-responsive cell line [28,29]. As shown in Fig.…”

Identification of candidate biomarkers for epithelial ovarian cancer metastasis using microarray data

“…Furthermore, THBS2 is one of ten signature genes associated with cell adhesion, and is associated with metastasis and poor overall survival time in patients with serous ovarian cancer (29). Downregulated by the inhibition of the Hedgehog signaling pathway, THBS1 is associated with ECM-ovarian cancer cell receptor interaction (30). The enrichment analysis performed in the present study demonstrated that THBS1 and THBS2 are associated with the cell adhesion and ECM-receptor interaction signaling pathways, suggesting they may serve key functions in EOC metastasis via regulating these two pathways.…”