Epigenetic regulation of liver cancer stem cells and establishment of a novel therapeutic approach

• Project/Area Number: 23689039
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Chiba University
• Principal Investigator: CHIBA Tetsuhiro 千葉大学, 医学(系)研究科(研究院), 講師 (00381583)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥25,480,000 (Direct Cost: ¥19,600,000、Indirect Cost: ¥5,880,000); Fiscal Year 2012: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000); Fiscal Year 2011: ¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000)
• Keywords: エピジェネティクス / 肝癌 / 肝臓 / 幹細胞 / 肝臓癌 / 癌幹細胞 / ポリコーム遺伝子 / DZNep / 癌幹細胞特異的治療法

Research Abstract

Polycomb group protein EZH2 is essential for the self-renewal of liver cancer stem cells. Short hairpin-RNA against EZH2 and 3-Deazaneplanocin A (DZNep) promotes the conversion toward differentiated progeny cells and reduced tumorigenic ability thorough the inhibition of H3K27 trimethylation (H3K27me3). We also conducted chromatin immunoprecipitation sequencing (ChIP-seq) analysis of normal hepatic stem cells using anti-H3K27me3 and anti-H3K4me3 antibodies, and successfully identified 562 bivalent genes. In combination with microarray data in the differentiation induction, candidate genes closely associated with hepatocytes and/or cholangiocytes were selected from bivalent genes. Since cancer-related genes were included among these genes, further analyses would be necessary to examine the role of these molecules in normal hepatic stem cells and liver cancer stem cells.

Research Products

• [Journal Article] Disulfiram eradicates tumor-initiating hepatocellular carcinoma cells in ROS-p38 MAPK pathway-dependent and -independent manners (2014)
  • Author(s): Chiba T, Suzuki E, Yuki K, Zen Y, Oshima M, Miyagi S, Saraya A, Koide S, Motoyama T, Ogasawara S, Ooka Y, Tawada A, Nakatsura T, Hayashi T, Yamashita T, Kaneko S, Miyazaki M, Iwama A, Yokosuka O
  • Journal Title: PLoS One Volume: 9(1) Issue: 1 Pages: e84807-e84807
  • DOI: 10.1371/journal.pone.0084807
  • Peer Reviewed
• [Journal Article] The TIF1β-HP1 System Maintains Transcriptional Integrity of Hematopoietic Stem Cells. (2014)
  • Author(s): Miyagi S, Koide S, Saraya A, Wendt GR, Oshima M, Konuma T, Yamazaki S, Mochizuki-Kashio M, Nakajima-Takagi Y, Wang C, Chiba T, Kitabayashi I, Nakauchi H, Iwama A.
  • Journal Title: Stem Cell Reports. Volume: 2 Issue: 2 Pages: 145-52
  • DOI: 10.1016/j.stemcr.2013.12.008
  • Peer Reviewed / Open Access
• [Journal Article] Natural history of postvascular-phase iso-enhanced lesions on the sonogram in chronic liver diseases (2014)
  • Author(s): Kondo T, Maruyama H, Sekimoto T, Shimada T, Takahashi M, Chiba T, Kanai F, Yokosuka O, Yamaguchi T
  • Journal Title: J Gastroenterol Hepatol Volume: 29(1) Issue: 1 Pages: 165-72
  • DOI: 10.1111/jgh.12449
  • Peer Reviewed
• [Journal Article] Effect of metformin on residual cells after chemotherapy in a human lung adenocarcinoma cell line. (2013)
  • Author(s): Kitazono, S., Takiguchi, Y., Ashinuma, H., Saito-Kitazono, M., Kitamura, A., Chiba, T., Sakaida, E., Sekine, I., Tada, Y., Kurosu, K., Sakao, S., Tanabe, N., Iwama, A., Yokosuka, O. and Tatsumi, K.
  • Journal Title: Int. J. Oncol. Volume: 43 Issue: 6 Pages: 1846-1854
  • DOI: 10.3892/ijo.2013.2120
  • Peer Reviewed
• [Journal Article] Efficacy of transcatheter arterial chemoembolization with miriplatin-lipiodol water-soluble contrast agent emulsion in patients with hepatocellular carcinoma (2013)
  • Author(s): Okimoto K, Ogasawara S, Chiba T, Ooka Y, Oobu M, Azemoto R, Kanogawa N, Motoyama T, Suzuki E, Tawada A, Yoshikawa M, Yokosuka O
  • Journal Title: Anticancer Res Volume: 33(12) Pages: 5603-9
  • Peer Reviewed
• [Journal Article] Metformin, a Diabetes Drug, Eliminates Tumor-Initiating Hepatocellular Carcinoma Cells. (2013)
  • Author(s): Saito, T., Chiba, T., Yuki, K., Zen, Y., Oshima, M., Koide, S., Motoyama, T., Ogasawara, S., Suzuki, E., Ooka, Y., Tawada, A., Tada, M., Kanai, F., Takiguchi, Y., Iwama, A. and Yokosuka, O.
  • Journal Title: PloS one Volume: 8 Issue: 7 Pages: e70010-e70010
  • DOI: 10.1371/journal.pone.0070010
  • Peer Reviewed
• [Journal Article] Gadoxetic acid-enhanced MRI compared with CT during angiography in the diagnosis of hepatocellular carcinoma (2013)
  • Author(s): Ooka Y, Kanai F, Okabe S, Ueda T, Shimofusa R, Ogasawara S, Chiba T, Sato Y, Yoshikawa M, Yokosuka O
  • Journal Title: Magn Reson Imaging Volume: 31(5) Issue: 5 Pages: 748-54
  • DOI: 10.1016/j.mri.2012.10.028
  • Peer Reviewed
• [Journal Article] Circulating cancer stem cells : a novel prognostic predictor of hepatocellular carcinoma (2013)
  • Author(s): Chiba T, Kanai F, Iwama A, Yokosuka O
  • Journal Title: Hepatobiliary Surg Nutr Volume: 2(1) Pages: 4-6
  • Peer Reviewed
• [Journal Article] Adherence to medication is a more important contributor to viral breakthrough in chronic hepatitis B patients treated with entecavir than in those with Lamivudine (2013)
  • Author(s): Kamezaki H, Kanda T, Arai M, Wu S, Nakamoto S, Chiba T, Maruyama H, Fujiwara K, Kanai F, Imazeki F, Nomura F, Yokosuka O
  • Journal Title: Int J Med Sci Volume: 10(5) Issue: 5 Pages: 567-74
  • DOI: 10.7150/ijms.5795
  • Peer Reviewed
• [Journal Article] Circulating cancer stem cells: a novel prognostic predictor of hepatocellular carcinoma. (2013)
  • Author(s): Chiba T, Kanai F, Iwama A, Yokosuka O.
  • Journal Title: Hepatobiliary Surg Nutr. Volume: 2 Pages: 4-6
  • Peer Reviewed
• [Journal Article] Aldehyde dehydrogenase 1 is associated with recurrence-free survival but not stem cell-like properties in hepatocellular carcinoma (2012)
  • Author(s): Suzuki E, Chiba T, Zen Y, Miyagi S, Tada M, Kanai F, Imazeki F, Miyazaki M, Iwama A, Yokosuka O
  • Journal Title: Hepatol Res Volume: 42(11) Issue: 11 Pages: 1100-11
  • DOI: 10.1111/j.1872-034x.2012.01028.x
  • Peer Reviewed
• [Journal Article] Ezh2 augments leukemogenecity by reinforcing differentiation blockage in acute myeloid leukemia (2012)
  • Author(s): Tanaka S
  • Journal Title: Blood Volume: 120 Issue: 5 Pages: 1107-17
  • DOI: 10.1182/blood-2011-11-394932
  • Peer Reviewed
• [Journal Article] Antiproliferative action of metformin in human lung cancer cell lines (2012)
  • Author(s): Ashinuma H, Takiguchi Y, Sakaida E, Sekine I, et al
  • Journal Title: Oncology Reports Volume: 28(1) Pages: 8-14
  • DOI: 10.3892/or.2012.1763
  • Peer Reviewed
• [Journal Article] 3-Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor-initiating hepatocellular carcinoma cells (2012)
  • Author(s): Chiba T, Suzuki E, Negishi M, Saraya A, Miyagi S, Konuma T, Tanaka S, Tada M, Kanai F, Imazeki F, Iwama A, Yokosuka O
  • Journal Title: International Journal of Cancer Volume: 130(11) Issue: 11 Pages: 2557-2567
  • DOI: 10.1002/ijc.26264
  • Peer Reviewed
• [Journal Article] 3-Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor-initiating hepatocellular carcinoma cells (2012)
  • Author(s): Chiba T, et al.
  • Journal Title: Int J Cancer Volume: 130 Pages: 2557-67
  • Peer Reviewed
• [Journal Article] Aldehyde dehydrogenase 1 is associated with recurrence free survival but notstem cell-like properties in hepatocellular carcinoma (2012)
  • Author(s): Chiba T, et al.
  • Journal Title: Hepatol Res Volume: (In press)
  • Peer Reviewed
• [Journal Article] Antiproliferative action of metformin in human lung cancer cell lines (2012)
  • Author(s): Ashinuma N, Chiba T, et al.
  • Journal Title: Oncol Rep Volume: (In press)
  • Peer Reviewed
• [Journal Article] The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3 K14 and required for fetal liver erythropoiesis (2011)
  • Author(s): Mishima Y, Chiba T, et al.
  • Journal Title: Blood Volume: 118 Pages: 2443-53
  • Peer Reviewed
• [Presentation] Prognosis of the hepatic nodules that show hypovascular in arterial phase and hypointense in hepatobiliary phase on gadoxetic acid enhanced MRI (2013)
  • Author(s): Ooka Y, Kanai F, Motoyama T, Ogasawara S, Suzuki E, Tawada A, Chiba T, Yokosuka O
  • Organizer: 2013年度米国肝臓学会総会(AASLD 2013)
  • Place of Presentation: 米国
  • Year and Date: 2013-11-02
• [Presentation] 肝癌幹細胞治療薬ジスルフィラムの有用性の検証 (2013)
  • Author(s): 鈴木英一郎、千葉哲博、元山天佑、小笠原定久、大岡美彦、太和田暁之、金井文彦、岩間厚志、横須賀收
  • Organizer: 第55回日本消化器病学会大会
  • Place of Presentation: 東京
  • Year and Date: 2013-10-09
• [Presentation] Intermediate stage におけるTACE 不応症例の治療戦略 (2013)
  • Author(s): 小笠原定久、大岡美彦、元山天佑、鈴木英一郎、太和田暁之、千葉哲博、金井文彦、横須賀收
  • Organizer: 第17回日本肝臓学会大会
  • Place of Presentation: 東京
  • Year and Date: 2013-10-09
• [Presentation] 当院における非B 非C 肝細胞癌の臨床像 (2013)
  • Author(s): 叶川直哉、小笠原定久、元山天佑、鈴木英一郎、大岡美彦、太和田暁之、千葉哲博、金井文彦、横須賀收
  • Organizer: 第17回日本肝臓学会大会
  • Place of Presentation: 東京
  • Year and Date: 2013-10-09
• [Presentation] バルーン下閉塞下肝動脈化学塞栓術(B-TACE)を用いたTACE 不能症例に対する肝細胞癌治療の経験 (2013)
  • Author(s): 中村昌人、大岡美彦、小笠原定久、元山天佑、鈴木英一郎、太和田暁之、千葉哲博、吉川正治、金井文彦、横須賀收
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2013-06-06
• [Presentation] EOB 造影MRI 肝細胞相で低信号となる乏血性肝細胞性結節の予後 (2013)
  • Author(s): 坂本大、大岡美彦、元山天佑、小笠原定久、鈴木英一郎、太和田暁之、千葉哲博、金井文彦、横須賀收
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2013-06-06
• [Presentation] 高度血小板減少を伴う進行肝細胞癌患者における化学療法導入のための部分脾動脈塞栓術および肝動脈化学塞栓術併用療法の有効性と安全性 (2013)
  • Author(s): 大岡美彦、金井文彦、元山天佑、小笠原定久、鈴木英一郎、太和田暁之、千葉哲博、横須賀收
  • Organizer: 第99回日本消化器病学会総会
  • Place of Presentation: 鹿児島
  • Year and Date: 2013-03-21
• [Presentation] 進行肝細胞癌におけるソラフェニブPD後の治療戦略 (2012)
  • Author(s): 小笠原定久、金井文彦、大岡美彦、元山天佑、太和田暁之、千葉哲博、横須賀收
  • Organizer: 第16回日本肝臓学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2012-10-11
• [Presentation] 幹細胞マーカーアルデヒド脱水素酵素1(ALDH1)の肝癌における解析 (2012)
  • Author(s): 鈴木英一郎、千葉哲博、横須賀收
  • Organizer: 第54回日本消化器病学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2012-10-10
• [Presentation] アルデヒド脱水素酵素1(ALDH1)の新規肝癌バイオマーカーとしての有用性の検討 (2012)
  • Author(s): 鈴木英一郎、千葉哲博、横須賀收
  • Organizer: 第48回日本肝癌研究会
  • Place of Presentation: 金沢
  • Year and Date: 2012-07-20
• [Presentation] EZH2 ablation is a novel therapeutic target for the eradication of tumor-initiating hepatocellular carcinoma cells (2012)
  • Author(s): Chiba T, Suzuki E, Motoyama T, Ogasawara S, Ooka Y, Tawada A, Kanai F, Iwama A, Yokosuka O
  • Organizer: 2012年度アジア太平洋肝臓学会議総会(APASL 2012)
  • Place of Presentation: 台湾
  • Year and Date: 2012-02-18
• [Presentation] EZH2 ablation is a novel therapeutic target for the eradication of tumor-initiating hepatocellular carcinoma cells (2012)
  • Author(s): 千葉哲博, ら
  • Organizer: 2012年度アジア太平洋肝臓学会議総会(APASL2012)
  • Place of Presentation: 台北
  • Year and Date: 2012-02-17
• [Presentation] 肝癌幹細胞に対するエピジェネティック治療の可能性 (2011)
  • Author(s): 千葉哲博, ら
  • Organizer: 2011年度日本消化器関連学会週間(JDDW2011)
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-21
• [Presentation] 肝癌幹細胞に対するエピジェネティック治療の可能性 (2011)
  • Author(s): 千葉哲博、岩間厚志、横須賀收
  • Organizer: 第53回日本消化器病学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-20
• [Presentation] 1 型アルデヒド脱水素酵素（ALDH1）の新規肝癌バイオマーカーとしての有用性の検討
  • Author(s): 鈴木英一郎、千葉哲博、金井文彦、元山天佑、小笠原定久、大岡美彦、太和田暁之、岩間厚志、横須賀收
  • Organizer: 第48回日本肝癌研究会
  • Place of Presentation: 金沢
• [Presentation] 肝癌幹細胞治療薬としてのジスルフィラムの有用性の検証
  • Author(s): 鈴木英一郎、千葉哲博、金井文彦、斉藤朋子、叶川直哉、元山天佑、小笠原定久、大岡美彦、太和田暁之、岩間厚志、横須賀收
  • Organizer: 第55回日本消化器病学会大会
  • Place of Presentation: 東京
• [Presentation] 肝癌幹細胞に対する糖尿病治療薬メトホルミンの作用機序の検討
  • Author(s): 斉藤朋子、千葉哲博、叶川直哉、元山天佑、小笠原定久、鈴木英一郎、大岡美彦、太和田暁之、岩間厚志、横須賀收
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: 東京
• [Patent(Industrial Property Rights)] 肝がん幹細胞阻害剤 (2013)
  • Inventor(s): 千葉哲博、鈴木英一郎、金井文彦、横須賀收
  • Industrial Property Rights Holder: 国立大学法人千葉大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-224722
  • Acquisition Date: 2013-05-23
• [Patent(Industrial Property Rights)] 肝がん幹細胞阻害剤 (2012)
  • Inventor(s): 千葉哲博、他3名
  • Industrial Property Rights Holder: 国立大学法人千葉大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-224722
  • Filing Date: 2012-10-10
  • Acquisition Date: 2013-05-23
• [Patent(Industrial Property Rights)] 肝がん幹細胞阻害剤 (2011)
  • Inventor(s): 千葉哲博, ら
  • Industrial Property Rights Holder: 千葉大学
  • Industrial Property Number: 2011-223639
  • Filing Date: 2011-10-11