Enhancer of Zeste Homolog 2 (EZH2) Promotes Progression of Cholangiocarcinoma Cells by Regulating Cell Cycle and Apoptosis

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• 作者：Shigeki Nakagawa MD (1)
  Hirohisa Okabe MD ; PhD (1)
  Yasuo Sakamoto MD ; PhD (1) (2)
  Hiromitsu Hayashi MD ; PhD (1)
  Daisuke Hashimoto MD ; PhD (1)
  Naomi Yokoyama (1)
  Keita Sakamoto MD (1)
  Hideyuki Kuroki MD (1)
  Kosuke Mima MD ; PhD (1)
  Hidetoshi Nitta MD ; PhD (1)
  Katsunori Imai MD ; PhD (1)
  Akira Chikamoto MD ; PhD (1)
  Masayuki Watanabe MD ; PhD (1)
  Toru Beppu MD ; PhD (1) (2)
  Hideo Baba MD ; PhD (1)
  
• 刊名：Annals of Surgical Oncology
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：20
• 期：3-supp
• 页码：667-675
• 全文大小：510 KB
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• 作者单位：Shigeki Nakagawa MD (1)
  Hirohisa Okabe MD, PhD (1)
  Yasuo Sakamoto MD, PhD (1) (2)
  Hiromitsu Hayashi MD, PhD (1)
  Daisuke Hashimoto MD, PhD (1)
  Naomi Yokoyama (1)
  Keita Sakamoto MD (1)
  Hideyuki Kuroki MD (1)
  Kosuke Mima MD, PhD (1)
  Hidetoshi Nitta MD, PhD (1)
  Katsunori Imai MD, PhD (1)
  Akira Chikamoto MD, PhD (1)
  Masayuki Watanabe MD, PhD (1)
  Toru Beppu MD, PhD (1) (2)
  Hideo Baba MD, PhD (1)
  
  1. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
  2. Department of Multidisciplinary Treatment for Gastroenterological Cancer, Kumamoto University Hospital, Kumamoto, Japan
  
• ISSN：1534-4681

文摘

Background Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2). When present in PRC2, EZH2 catalyzes trimethylation on lysine 27 residue of histone H3, resulting in epigenetic silencing of gene expression and cancer progression. We investigated the expression and function of EZH2 in intrahepatic and extrahepatic cholangiocarcinoma (ICC and ECC). Methods The influence of EZH2 on cell growth and apoptosis was assessed by knockdown experiments. Target gene of EZH2 was searched by quantitative RT-PCR. Clinical significance of EZH2 in 86 cholangiocarcinoma patients (45 ICC and 41 ECC) who underwent curative surgery was examined by immunohistochemistry. Results In vitro analysis, knockdown of EZH2 reduced cell growth, induced G1 arrest, and induced apoptosis, as confirmed by Annexin V staining and increased sub-G1 populations in cholangiocarcinoma cell lines. The expression levels of p16 INK4a and p27 KIP1 were remarkably increased by knockdown of EZH2 in these cell lines. In immunohistochemical study, EZH2 upregulation correlated with tumor diameter (p?=?0.0103) in ICC, lymph node metastasis (p?=?0.0292) in ECC, and Ki67 index in both ICC (p?=?0.0364) and ECC (p?=?0.0017). In addition, EZH2 expression was correlated with poor prognosis in both ICC (p?=?0.0447) and ECC (p?=?0.0227). Conclusions The current study demonstrated relationships between EZH2 expression and acceleration of the cell cycle and antiapoptosis, and poor prognosis in cholangiocarcinoma. These results suggest that EZH2 may represent a potential therapeutic target in patients with cholangiocarcinoma.