Research Papers:

Addiction of pancreatic cancer cells to zinc-finger transcription factor ZIC2

Shingo Inaguma, Hideaki Ito, Miho Riku, Hiroshi Ikeda and Kenji Kasai _

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Oncotarget. 2015; 6:28257-28268. https://doi.org/10.18632/oncotarget.4960

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Shingo Inaguma1, Hideaki Ito1, Miho Riku1, Hiroshi Ikeda1 and Kenji Kasai1

1 Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan

Correspondence to:

Kenji Kasai, email:

Shingo Inaguma, email:

Keywords: ZIC2, GLI1, ANXA8, FGFR3, apoptosis

Received: June 06, 2015 Accepted: July 03, 2015 Published: July 22, 2015


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.

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