Elucidation of liver carcinogenesis mechanism by epigenetic reprogramming.

• Project/Area Number: 24659593
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: General surgery
• Research Institution: Yokohama City University
• Principal Investigator: SEKINE Keisuke 横浜市立大学, 医学部, 助教 (00323569)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 癌 / エピジェネティクス / リプログラミング

Research Abstract

As a result of introduction of the 4 factors to the HCC cell lines, colonies of iPS cell-like is formed after about 2 weeks. The established clones were investigated by morphological observation, gene expression analysis and the transplantation into immunodeficient mice. Expression of hepatocyte marker HNF4 in comparison with HCC cell lines were decreased. And increased expression of Sox2, undifferentiated marker, was observed. However, the expression of undifferentiated markers were lower compared with iPS cells. To verify the presence or absence of teratoma formation capability, clones were transplanted into the testes of immunodeficient mice (NOD / scid). However no teratoma formation was observed from clones that were established in this study.

Research Products

• [Journal Article] Tropism of cancer stem cells to a specific distant organ (2014)
  • Author(s): Okuda R, Sekine K, Hisamatsu D, Ueno Y, Takebe T, Zheng YW, Taniguchi H
  • Journal Title: In Vivo Volume: 28(3) Pages: 361-5
  • Peer Reviewed
• [Journal Article] The CD133+CD44+ Precancerous Subpopulation of Oval Cells is a Therapeutic Target for Hepatocellular (2014)
  • Author(s): Zheng YW, Tsuchida T, Shimao T, Li B, Takebe T, Zhang RR, Sakurai Y, Ueno Y, Sekine K, Ishibashi N, Imajima M, Tanaka T, Taniguchi H
  • Journal Title: Carcinoma Stem Cells Dev Volume: (in press)
  • Peer Reviewed
• [Journal Article] Fluorescent labeling and visualization of human induced pluripotent stem cells with the use of transcription activator-like effector nucleases (2014)
  • Author(s): Sekine K, Takebe T, Taniguchi H.
  • Journal Title: Transplant Proc Volume: 46 Pages: 1205-1207
  • DOI: 10.1016/j.transproceed.2014.02.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ring1B Promotes Hepatic Stem/Progenitor Cell Expansion via Simultaneous Suppression of Cdkn1a and Cdkn2a. (2014)
  • Author(s): Koike H, Ueno Y, Naito T, Shiina T, Nakata S, Ouchi R, Obana Y, Sekine K, Zheng YW, Takebe T, Isono K, Koseki H, Taniguchi H
  • Journal Title: Hepatology. Volume: (Epub ahead of print) Pages: 323-333
  • DOI: 10.1002/hep.27046
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Engineering of human hepatic tissue with functional vascular networks (2014)
  • Author(s): Takebe T, Koike N, Sekine K, Fujiwara R, Amiya T, Zheng YW, Taniguchi H
  • Journal Title: Organogenesis Volume: 10(2)(Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant (2014)
  • Author(s): Takanori Takebe*, Ran-Ran Zhang, Hiroyuki Koike, Masaki Kimura, Emi Yoshizawa, Masahiro Enomura, Keisuke Sekine, Hideki Taniguchi*(*: Correspondence)
  • Journal Title: Nat Protoc. Volume: 9(2) Pages: 396-409
  • DOI: 10.1038/nprot.2014.020
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Evidence of a Sophisticatedly Heterogeneous Population of Human Umbilical Vein Endothelial Cells (2014)
  • Author(s): Zheng YW, Nie YZ, Tsuchida T, Zhang RR, Aoki K, Sekine K, Ogawa M, Takebe T, Ueno Y, Sakakibara H, Hirahara F, Taniguchi H
  • Journal Title: Transplant Proc. Volume: 46 Pages: 1251-1253
  • DOI: 10.1016/j.transproceed.2013.11.077
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of Proliferating Human Hepatic Cells from Human Induced Pluripotent Stem Cells. (2014)
  • Author(s): Zhang RR, Takebe T, Sekine K, Koike H, Zheng YW, Taniguchi H
  • Journal Title: Transplant Proc. Volume: 46(4) Pages: 1201-1204
  • DOI: 10.1016/j.transproceed.2013.12.021
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The development of humanized liver with Rag1 knockout rats. (2014)
  • Author(s): Tsuchida T, Zheng YW, Zhang RR, Takebe T, Ueno Y, Sekine K, Taniguchi H
  • Journal Title: Transplant Proc. Volume: 46 Pages: 1191-1193
  • DOI: 10.1016/j.transproceed.2013.12.026
  • Peer Reviewed / Open Access
• [Journal Article] High-resolution intravital imaging for monitoring the transplanted islet in mice. (2014)
  • Author(s): Takahashi Y, Takebe T, Enomura M, Koike N, Lee S, Nemeno JG, Sekine K, Lee JI, Taniguchi H.
  • Journal Title: Transplant Proc Volume: 46 Pages: 1166-1168
  • DOI: 10.1016/j.transproceed.2013.11.089
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Vascularized and functional human liver from an iPSC-derived organ bud transplant (2014)
  • Author(s): Takanori Takebe*, Keisuke Sekine, Masahiro Enomura, Hiroyuki Koike, Ran-Ran Zhang, Yasuharu Ueno, Yun-Wen Zheng, Naoto Koike, Shinsuke Aoyama, Yasuhisa Adachi, Hideki Taniguch*(*: Correspondence)
  • Journal Title: Nature Volume: 499 Pages: 481-4
  • DOI: 10.1038/nature12271
  • NAID: 40020351046
  • Peer Reviewed
• [Journal Article] Tropism of cancer stem cells to a specific distant organ (2014)
  • Author(s): Okuda R, Sekine K, Hisamatsu D, Ueno Y, Takebe T, Zheng YW, Taniguchi H.
  • Journal Title: In Vivo Volume: in press
  • Peer Reviewed
• [Journal Article] The CD133+CD44+ Precancerous Subpopulation of Oval Cells is a Therapeutic Target for Hepatocellular Carcinoma (2014)
  • Author(s): Zheng YW, Tsuchida T, Shimao T, Li B, Takebe T, Zhang RR, Sakurai Y, Ueno Y, Sekine K, Ishibashi N, Imajima M, Tanaka T, Taniguchi H.
  • Journal Title: Stem Cells Dev. Volume: in press
  • Peer Reviewed
• [Journal Article] Fluorescent labeling and visualization of human induced pluripotent stem cells with the use of transcription activatore like effector nucleases (2014)
  • Author(s): Sekine K, Takebe T, Taniguchi H.
  • Journal Title: Transplant Proc. Volume: in press
  • Peer Reviewed
• [Journal Article] Ring1B promotes hepatic stem/ progenitor cell expansion via simultaneous suppression of Cdkn1a and Cdkn2a. (2014)
  • Author(s): Koike H, Ueno Y, Naito T, Shiina T, Nakata S, Ouchi R, Obana Y, Sekine K, Zheng YW,Takebe T, Isono KI, Koseki H, Taniguchi H.
  • Journal Title: Hepatology Volume: in press
  • Peer Reviewed
• [Journal Article] Engineering of human hepatic tissue with functional vascular networks. (2014)
  • Author(s): Takebe T, Koike N, Sekine K, Fujiwara R, Amiya T, Zheng YW, Taniguchi H.
  • Journal Title: Organogenesis. Volume: in press
  • Peer Reviewed
• [Journal Article] Efficient generation of pancreatic β-cell spheroids in a simulated microgravity culture system. (2013)
  • Author(s): Tanaka H
  • Journal Title: Biomaterials Volume: 34 Pages: 5785-5791
  • DOI: 10.1016/j.biomaterials.2013.04.003
  • Peer Reviewed
• [Journal Article] Vitamin D Receptor in osteoblasts Is a negative regulator of bone mass control (2013)
  • Author(s): Yamamoto Y, Yoshizawa T, Fukuda T, Shirode-Fukuda Y, Yu T, Sekine K, Sato T, Kawano H, Aihara K, Naka michi Y, Watanabe T, Shindo M, Inoue K, Inoue E, Tsuji N, Hoshino M, Karsenty G, Metzger D, Chambon P, Kato S, Imai Y.
  • Journal Title: Endocrinology Volume: 154 Pages: 1008-1020
  • DOI: 10.1210/en.2012-1542
  • Peer Reviewed
• [Journal Article] Highly efficient generation of definitive endoderm lineage from human induced pluripotent cells (2013)
  • Author(s): Sekine K
  • Journal Title: Transplant Proc. Volume: 44(4) Pages: 1127-1129
  • DOI: 10.1016/j.transproceed.2012.03.001
  • Peer Reviewed
• [Journal Article] Establishment of Automated Culture System for Induced Pluripotent Stem Cells (2012)
  • Author(s): Koike H
  • Journal Title: BMC biotechnology Volume: 12 Pages: 81-81
  • DOI: 10.1186/1472-6750-12-81
  • Peer Reviewed
• [Journal Article] Inhibition of Stabilin-2 elevates the circulating hyaluronic acid level and prevents tumor metastasis (2012)
  • Author(s): Hirose, Y., Saijou, E., Sugan,o Y., Takeshita, F., Nishimura, S., Nonaka, H., Chen, Y.R., Sekine, K., Kido, T., Nakamura, T., Kato, S., Kanke, T., Nakamura, K., Nagai, R., Ochiya, T., Miyajima, A.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 109 Pages: 4263-4268
  • DOI: 10.1073/pnas.1117560109
  • Peer Reviewed
• [Journal Article] Regenerative medicine approach as an alternative treatment to islet transplantation (2012)
  • Author(s): Sekine K
  • Journal Title: Transplant Proc Volume: 44(4) Pages: 1104-1106
  • DOI: 10.1016/j.transproceed.2012.03.020
  • Peer Reviewed
• [Journal Article] elf-organization of human hepatic organoid by recapitulating organogenesis in vitro. (2012)
  • Author(s): Takebe T
  • Journal Title: Transplant Proc Volume: 44(4) Pages: 1018-1020
  • DOI: 10.1016/j.transproceed.2012.02.007
  • Peer Reviewed
• [Journal Article] Generation of human vascular network in vitro. (2012)
  • Author(s): Takebe T
  • Journal Title: Transplant Proc Volume: 44(4) Pages: 1130-1133
  • DOI: 10.1016/j.transproceed.2012.03.039
  • Peer Reviewed
• [Journal Article] Basics and applications of stem cells in the pancreas (2012)
  • Author(s): Sekine K, Taniguchi H
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 19 Pages: 594-599
  • DOI: 10.1007/s00534-012-0545-3
  • NAID: 10031126973
• [Presentation] 膵癌幹細胞の系譜解析に向けたin vitroアッセイ系の構築 (2014)
  • Author(s): 久松大介、奥田諒、関根圭輔、上野康晴、谷口英樹
  • Organizer: 第13回日本再生医療学会総会
  • Place of Presentation: 京都
• [Presentation] 膵癌幹細胞の系譜解析に向けたin vitroアッセイ系の構築 (2014)
  • Author(s): 久松大介、奥田 諒、関根圭輔、上野康晴、谷口英樹
  • Organizer: 第13回日本再生医療学会総会
  • Place of Presentation: 国立京都国際会館(京都府)
• [Presentation] Pdx1陽性細胞は高い腫瘍形成能とスフィア形成能を有する癌幹細胞である (2013)
  • Author(s): 奥田諒、関根圭輔、孫略、坪井康次、谷口英樹
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 神奈川
• [Presentation] 膵幹/前駆細胞の膵癌幹細胞への形質転換プロセスの解析 (2013)
  • Author(s): 関根圭輔、孫略、奥田諒、谷口英樹
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 神奈川
• [Presentation] ヒト膵癌幹細胞における治療抵抗性機構の解析 (2013)
  • Author(s): 星野小百合、関根圭輔、孫略、中田晋、寺崎哲也、森永総一郎、宮城洋平、遠藤格、横瀬智之、倉田昌直、上野康晴、谷口英樹
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 神奈川
• [Presentation] Fluorescence visualizaiton of human induced pluripotent stem cells using transcription activator-like(TAL) effector nucleases (2013)
  • Author(s): Sekine K, Takebe T, Zhang R, Taniguchi H
  • Organizer: The 13th Congress of the Asian Society of Transplantation
  • Place of Presentation: Kyoto, Japan
• [Presentation] Targeted proteomic absolute quantification on transporters of human pancreatic cancer cells with gemcitabine-resistance (2013)
  • Author(s): Ueno Y, Hoshino S, Tsuchida N, Nakata S, Uchida Y, Sekine K, Zheng YW, Kurata M, Morinaga S, Miyagi Y, Yokose T, Endo I, Terasaki T, Hirano H, Taniguchi H
  • Organizer: HUPO 12th annual world congress
  • Place of Presentation: Yokohama, Japan
• [Presentation] Targeted proteomic absolute quantification on transporters of human pancreatic cancer cells with gemcitabine-resistance. (2013)
  • Author(s): Ueno Y, Hoshino S, Tsuchida N, Nakata S, Uchida Y, Sekine K, Zheng YW, Kurata M, Morinaga S, Miyagi Y, Yokose T, Endo I, Terasaki T, Hirano H, Taniguchi H
  • Organizer: HUPO 12th annual world congress.
  • Place of Presentation: パシフィコ横浜(神奈川)
• [Presentation] 膵癌幹細胞のin vitroアッセイ系の解析 (2012)
  • Author(s): 奥田諒、孫略、関根圭輔、松井智栄美、坪井康次、谷口英樹
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] 膵癌モデルマウスを用いた膵癌幹細胞の細胞系譜解析 (2012)
  • Author(s): 孫略、奥田諒、関根圭輔、盛武敬、坪井康次、谷口英樹
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 膵肝/前駆細胞の膵癌幹細胞への形質転換プロセスの解析 (2012)
  • Author(s): 関根圭輔、孫略、奥田諒、谷口英樹
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Identification of pancreatic stem/progenitor cells expressing PDX1 reside in the CD133 positive pancreatic duct (2012)
  • Author(s): Sekine K, Ishikawa M, Takebe T, Suzaki A, Kawashimo K, Matsui C, Taniguchi H
  • Organizer: International Society for Stem Cell Research 10^<th> annual meeting
  • Place of Presentation: Yokohama,Japan
• [Presentation] 膵癌モデルマウスを用いた膵癌幹細胞の細胞系譜解析 (2012)
  • Author(s): 関根圭輔、孫略、奥田諒、谷口英樹
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌 (北海道)
• [Presentation] 膵肝/前駆細胞の膵癌幹細胞への形質転換プロセスの解析 (2012)
  • Author(s): 孫略、奥田諒、関根圭輔、盛武 敬、 坪井 康次、 谷口 英樹
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌 (北海道)
• [Presentation] Creation of vascularized human organ from induced pluripotent stem cells. (2012)
  • Author(s): Takebe T, Sekine K, Enomura M, Suzuki Y, Koike H, Zhang R, Koike N, Ueno Y, Zheng Y, Taniguchi H
  • Organizer: International Society for Stem Cell Research 10th annual meeting.
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] Self-renewal versus differentiation as well as the liver repopulation capability of human hepatic stem cells. (2012)
  • Author(s): Zheng Y, Li B, Zhang R, Kimura M, Tsuchida T, Takebe T, Ueno Y, Sekine K, Taniguchi H
  • Organizer: International Society for Stem Cell Research 10th annual meeting.
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] Identification of pancreatic stem/progenitor cells expressing PDX1 reside in the CD133 positive pancreatic duct. (2012)
  • Author(s): Sekine K, Ishikawa M, Takebe T, Suzaki A, Kawashimo K, Matsui C, Taniguchi H
  • Organizer: International Society for Stem Cell Research 10th annual meeting.
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] 膵幹細胞を起点とした膵発癌プロセスの細胞系譜的解析 (2012)
  • Author(s): 関根圭輔、松井智栄美、孫略、長久紗耶佳、田中慎、武部貴則、谷口英樹
  • Organizer: 第11回日本再生医療学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] 多能性幹細胞を用いた機能的なヒト臓器の創出 (2012)
  • Author(s): 武部貴則、関根圭輔、江野村允宏、小池博之、張冉冉、三橋優澄、上野康晴、鄭允文、谷口英樹
  • Organizer: 第11回日本再生医療学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] 多能性幹細胞を用いた機能的なヒト臓器の創出 (2012)
  • Author(s): 武部貴則、関根圭輔、江野村允宏、小池博之、張冉冉、木村昌樹、魚返拓則、吉澤絵美、川又史佳、上野康晴、鄭允文、小池直人、谷口英樹
  • Organizer: 第39回日本臓器保存生物医学会学術集会
  • Place of Presentation: コラッセふくしま(福島県)
• [Presentation] ヒト微小血管網を有する膵島様組織の創出 (2012)
  • Author(s): 高橋禎暢、江野村允宏、武部貴則、関根圭輔、小池直人、田中寛康、谷口英樹
  • Organizer: 第39回日本臓器保存生物医学会学術集会
  • Place of Presentation: コラッセふくしま(福島県)
• [Presentation] 膵幹細胞を起点とした膵発癌プロセスにおける膵癌幹細胞の細胞系譜的解析
  • Author(s): 関根圭輔、孫略、上野康晴、谷口英樹
  • Organizer: 第22 回日本サイトメトリー学会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪府)
  • Invited
• [Presentation] ヒトiPSを用いたファーマコセロミクス基盤技術の開発
  • Author(s): 谷口英樹、武部貴則、関根圭輔、青山晋輔、安達弥永
  • Organizer: 第127回日本薬理学会関東部会シンポジウム
  • Place of Presentation: 東京国際フォーラム(東京都)
  • Invited