title: 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: 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 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.
authors.affiliation: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Department of Biostatistics & Epidemiology, School of Public Health, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Quqin
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Dengliang
authors.initials: D
authors.lastname: Huang
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Shi
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Weilong
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Libin
authors.initials: L
authors.lastname: Deng
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Runwei
authors.initials: R
authors.lastname: Yan
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas, United States of America.
authors.forename: Hai
authors.initials: H
authors.lastname: Rao
authors.affiliation: Department of Obstetrics and Gynecology, General Hospital of Beijing Aeronautics, Beijing, China.
authors.forename: Guolan
authors.initials: G
authors.lastname: Gao
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Luo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039663:Integrin beta4 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: D000970:Antineoplastic Agents; C551027:GANT 61; C400551:GLI1 protein, human; C059834:ITGB4 protein, human; D039663:Integrin beta4; D011725:Pyridines; D011743:Pyrimidines; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human