title: Addiction of pancreatic cancer cells to zinc-finger transcription factor ZIC2.
abstract: Activity of GLI transcription factors of Hedgehog signaling is key for various cancer cell properties, especially in pancreatic ductal adenocarcinoma (PDAC). Zinc-finger transcriptional regulators ZIC1 to ZIC5 of ZIC gene family were demonstrated to associate with GLI to increase the nuclear accumulation and transcriptional activity of GLI. Notwithstanding this supportive role for GLI-dependent transcription, it was not fully understood whether ZIC plays an independent role in cancer cell biology. Here, we found that ZIC2 is indispensable in the regulation of PDAC cell apoptosis. We found that human PDAC cell lines uniquely express ZIC2. ZIC2 knockdown induced PDAC cell apoptosis; conversely, ZIC2 over-expression enhanced the cellular proliferation. Through a comprehensive screening, we identified fibroblast growth factor receptor 3 (FGFR3) and ANNEXIN A8 (ANXA8) as genes up-regulated by ZIC2 in PDAC cells. The forced expression of these two genes cooperatively rescued the apoptosis of ZIC2-knockdown cells. Immunohistochemical analyses further supported the correlation of ZIC2 expression and these genes in human pancreata harboring PDAC. Intriguingly, the ZIC2-mediated up-regulation of FGFR3 and ANXA8 was indicated to be GLI -independent. This evidence highlights the indispensable role of ZIC2 in regulating cellular proliferation and apoptosis during PDAC development and suggests a potential therapeutic target for PDAC.
authors: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors: Shingo
authors: S
authors: Inaguma
authors: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors: Hideaki
authors: H
authors: Ito
authors: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors: Miho
authors: M
authors: Riku
authors: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors: Hiroshi
authors: H
authors: Ikeda
authors: Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors: Kenji
authors: K
authors: Kasai
mesh_terms: D017302:Annexins / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D000071676:Zinc Finger Protein GLI1
chemical_list: D017302:Annexins; C400551:GLI1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; C491812:ZIC2 protein, human; D000071676:Zinc Finger Protein GLI1; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: ANXA8; FGFR3; GLI1; ZIC2; apoptosis