Drug screening for cholangiocarcinoma targeting the epigenetical mechanism of cancer progression

• Project/Area Number: 15K10191
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: CHIKAMOTO Akira 熊本大学, 医学部附属病院, 准教授 (10419640)
• Co-Investigator(Kenkyū-buntansha): 美馬 浩介 熊本大学, 医学部附属病院, 非常勤診療医師 (00546559) ; 中川 茂樹 熊本大学, 医学部附属病院, 医員 (10594872) ; 岡部 弘尚 熊本大学, 医学部附属病院, 助教 (40573621) ; 林 洋光 熊本大学, 医学部附属病院, 非常勤診療医師 (80625773)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肝内胆管癌 / EZH2 / VASH1 / 血管新生 / 細胞増殖 / Notch1 / DZNep / 胆管癌 / 細胞周期 / アポトーシス / Angiogenesis

Outline of Final Research Achievements

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and regulate tumor malignancy by gene silencing via histone methylation. In this study, we investigate the role of EZH2 in angiogenesis of intrahepatic cholangiocarcinoma (ICC). The influence of EZH2 on tumor angiogenesis and the prognostic significance of EZH2 and VASH1 expression was also examined in ICC cohort by IHC.
By bioinformatical analysis, EZH2 was associated with several angiogenesis gene set in public database. We also find that EZH2 suppress VASH1 expression in vitro assay and IHC study. In IHC analysis. EZH2-high/VASH1-low status was independently associated with poor disease-free survival (P=0.019) and poor overall survival (P=0.0055). The current study demonstrated that high EZH2 expression was associated with activation of tumor angiogenesis, and the EZH2 mediated angiogenesis pathway predicts the prognosis of patients with ICC.

Research Products

• [Journal Article] Prognostic impacts of postoperative complications in patients with intrahepatic cholangiocarcinoma after curative operations. (2017)
  • Author(s): Tatsunori Miyata, Yoichi Yamashita, Takanobu Yamao, Naoki Umezaki, Masayo Tsukamoto, Yuki Kitano, Kensuke Yamamura, Kota Arima, Takayoshi Kaida, Shigeki Nakagawa, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Takatoshi Ishiko, Hideo Baba.
  • Journal Title: Int J Clin Oncol Volume: - Issue: 3 Pages: 526-532
  • DOI: 10.1007/s10147-017-1099-9
  • Peer Reviewed
• [Journal Article] Preoperative high SUVmax, associated with glucose transporter 1, predicts poor prognosis in pancreatic cancer. (2017)
  • Author(s): Chikamoto A, Inoue R, Komohara Y, Sakamaki K, Hashimoto D, Shiraishi S, Takamori H, Yamashita Y, Yoshida N, Yamanaka T, Yamashita Y, Baba H
  • Journal Title: Ann Surg Oncol Volume: in press Issue: 7 Pages: 2040-2046
  • DOI: 10.1245/s10434-017-5799-1
  • Peer Reviewed
• [Journal Article] C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA. (2016)
  • Author(s): Kaida T, Nitta H, Kitano Y, Yamamura K, Arima K, Izumi D, Higashi T, Kurashige J, Imai K, Hayashi H, Iwatsuki M, Ishimoto T, Hashimoto D, Yamashita Y, Chikamoto A, Imanura T, Ishiko T, Beppu T, Baba H.
  • Journal Title: Oncotarget. Volume: 20(7) Issue: 51 Pages: 84798-84809
  • DOI: 10.18632/oncotarget.12656
  • Peer Reviewed
• [Journal Article] Statin attenuates cell proliferative ability via TAZ (WWTR1) in hepatocellular carcinoma. (2016)
  • Author(s): Higashi T, Hayashi H, Kitano Y, Yamamura K, Kaida T, Arima K, Taki K, Nakagawa S, Okabe H, Nitta H, Imai K, Hashimoto D, Chikamoto A, Beppu T, Baba H.
  • Journal Title: Med Oncol. Volume: 33(11) Issue: 11 Pages: 123-123
  • DOI: 10.1007/s12032-016-0845-6
  • Peer Reviewed
• [Journal Article] Heterogeneity of KRAS Mutations in Pancreatic Ductal Adenocarcinoma (2016)
  • Author(s): Hashimoto D, Arima K, Yokoyama N, Chikamoto A, Taki K, Inoue R, Kaida T, Higashi T, Nitta H, Ohmuraya M, Hirota M, Beppu T, Baba H
  • Journal Title: Pancreas Volume: 45 Issue: 8 Pages: 1111-1114
  • DOI: 10.1097/mpa.0000000000000624
  • Peer Reviewed / Open Access
• [Journal Article] An Imbalance in TAZ and YAP Expression in Hepatocellular Carcinoma Confers Cancer Stem Cell-like Behaviors Contributing to Disease Progression. (2015)
  • Author(s): Hayashi H, Higashi T, Yokoyama N, Kaida T, Sakamoto K, Fukushima Y, Ishimoto T, Kuroki H, Nitta H, Hashimoto D, Chikamoto A, Oki E, Beppu T, Baba H.
  • Journal Title: Cancer Res. Volume: 75(22) Issue: 22 Pages: 4985-97
  • DOI: 10.1158/0008-5472.can-15-0291
  • Peer Reviewed / Open Access
• [Journal Article] Significance of P-cadherin overexpression and possible mechanism of its regulation in intrahepatic cholangiocarcinoma and pancreatic cancer. (2015)
  • Author(s): Sakamoto K, Imai K, Higashi T, Taki K, Nakagawa S, Okabe H, Nitta H, Hayashi H, Chikamoto A, Ishiko T, Beppu T, Baba H.
  • Journal Title: Cancer Sci Volume: 106(9) Issue: 9 Pages: 1153-62
  • DOI: 10.1111/cas.12732
  • Peer Reviewed
• [Journal Article] Scoring system based on tumor markers and Child-Pugh classification for HCC patients who underwent liver resection. (2015)
  • Author(s): Nakagawa S, Hayashi H, Nitta H, Okabe H, Sakamoto K, Higashi T, Kuroki H, Imai K, Hashimoto D, Sakamoto Y, Chikamoto A, Beppu T, Baba H.
  • Journal Title: Anticancer Res Volume: 35(4) Pages: 2157-63
  • Peer Reviewed
• [Journal Article] Enhancer of Zeste Homolog 2 (EZH2) Promotes Progression of Cholangiocarcinoma Cells by Regulating Cell Cycle and Apoptosis. (2013)
  • Author(s): Nakagawa S, Okabe H, Sakamoto Y, Hayashi H, Hashimoto D, Yokoyama N, Sakamoto K, Kuroki H, Mima K, Nitta H, Imai K, Chikamoto A, Watanabe M, Beppu T, Baba H.
  • Journal Title: Ann Surg Oncol Volume: 3 Issue: S3 Pages: 667-675
  • DOI: 10.1245/s10434-013-3135-y
  • Peer Reviewed
• [Presentation] A stromal liver gene signature predictive of HCC risk across all liver disease etiologies (2018)
  • Author(s): Shigeki Nakagawa, Naoki Umesaki, Takanobu Yamao Yuki Kitano, Kensuke Yamamura, Kota Arima, Tatsunori Miyata, Takayoshi Kaida, Yujin Hoshida, Katsunori Imai,Daisuke Hashimoto, Yoichi Yamashita, Akira Chikamoto, Hideo Baba
  • Organizer: AACR 2018
  • Int'l Joint Research
• [Presentation] 肝細胞癌における多中心性及び肝内転移再発予測の為のMolecular gene signatureの検討 (2017)
  • Author(s): 中川茂樹、梅崎直紀、山尾宣暢、北野雄希、山村謙介、宮田辰徳、美馬浩介、今井克憲、橋本大輔、山下洋市、近本亮、馬場秀夫
  • Organizer: 第72回日本消化器外科学会総会