Inflammation related carcinogenesis by spiral cell transformation using in vitro chronic colitis model

• Project/Area Number: 15H04808
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: TSUCHIYA Kiichiro 東京医科歯科大学, 医学部附属病院, 准教授 (40376786)
• Co-Investigator(Kenkyū-buntansha): 大島 茂 東京医科歯科大学, 医学部附属病院, 助教 (50376787) ; 渡辺 守 (渡邉 守) 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10175127)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: Atoh1 / 炎症発癌 / 自然免疫応答 / 持続炎症刺激モデル / 持続炎症 / 炎症性腸疾患 / シグナルスパイラル

Outline of Final Research Achievements

Patients with ulcerative colitis are increasing in Japan, since it has been concerned the increase of the patients with UC-related colon cancer. However, the molecular mechanism of UC-related carcinogenesis is still unclear. In this study, we therefore built a continuation inflammation stimulation model using the primary culture system of the mouse colonic epithelium stem cell for the first time in the world. We then found that innate immuno-responce was in a spiral state by stimulation for a long term, indicating that this model might be UC model. In addition, we identified molecular mechanism of mucinous cancer formation during UC-related carcinogenesis, which has more malignant potential.

Research Products

• [Journal Article] Single cell analysis of Crohn’s disease patient-derived small intestinal organoids reveals disease activity-dependent modification of stem cell properties (2018)
  • Author(s): Suzuki Kohei、Murano Tatsuro、Shimizu Hiromichi、Ito Go、Nakata Toru、Fujii Satoru、Ishibashi Fumiaki、Kawamoto Ami、Anzai Sho、Kuno Reiko、Kuwabara Konomi、Takahashi Junichi、Tsuchiya Kiichiro、Nakamura Tetsuya、Ohtsuka Kazuo、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: Journal of Gastroenterology Volume: 印刷中 Issue: 9 Pages: 1035-1047
  • DOI: 10.1007/s00535-018-1437-3
  • Peer Reviewed / Open Access
• [Journal Article] Contribution of ATOH1 + Cells to the Homeostasis, Repair, and Tumorigenesis of the Colonic Epithelium (2018)
  • Author(s): Ishibashi Fumiaki、Shimizu Hiromichi、Nakata Toru、Fujii Satoru、Suzuki Kohei、Kawamoto Ami、Anzai Sho、Kuno Reiko、Nagata Sayaka、Ito Go、Murano Tatsuro、Mizutani Tomohiro、Oshima Shigeru、Tsuchiya Kiichiro、Nakamura Tetsuya、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: Stem Cell Reports Volume: 10 Issue: 1 Pages: 27-42
  • DOI: 10.1016/j.stemcr.2017.11.006
  • Peer Reviewed / Open Access
• [Journal Article] Novel polyubiquitin imaging system, PolyUb-FC, reveals that K33-linked polyubiquitin is recruited by p62/SQSTM1. (2017)
  • Author(s): Yoichi Nibe, Shigeru Oshima, Masanori Kobayashi, Chiaki Maeyashiki, Yu Matsuzawa, Kana Otsubo, Hiroki Matsuda, Emi Aonuma, Yasuhiro Nemoto, Takashi Nagaishi, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Shinichiro Nakada, Mamoru Watanabe
  • Journal Title: Autophagy. Volume: 22 Issue: 2 Pages: 1-43
  • DOI: 10.1080/15548627.2017.1407889
  • Peer Reviewed / Open Access
• [Journal Article] Long-term inflammation transforms intestinal epithelial cells of colonic organoids. (2017)
  • Author(s): Hibiya S, Tsuchiya K, Hayashi R, Horita N, Watanabe S, Shirasaki T, Nishimura R, Kimura N, Nishimura T, Gotoh N, Oshima S, Okamoto R, Nakamura T, Watanabe M
  • Journal Title: J Crohns Colitis. Volume: 61 Pages: 621-630
  • DOI: 10.1093/ecco-jcc/jjw186
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] HADHA, the alpha subunit of the mitochondrial trifunctional protein,is involved in long-chain fatty acid-induced autophagy in intestinal epithelial cells. (2017)
  • Author(s): Maeyashiki C, Oshima S, Otsubo K, Kobayashi M, Nibe Y, Matsuzawa Y, Onizawa M, Nemoto Y, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Watanabe M
  • Journal Title: Biochem Biophys Res Commun. Volume: 484 Issue: 3 Pages: 636-641
  • DOI: 10.1016/j.bbrc.2017.01.159
  • Peer Reviewed
• [Journal Article] Regulation of intestinal homeostasis by theulcerative colitis-associated gene RNF186. (2017)
  • Author(s): Fujimoto K, Kinoshita M, Tanaka H, Okuzaki D, Shimada Y, Kayama H, Okumura R, Furuta Y, Narazaki M, Tamura A, Hatakeyama S, Ikawa M, Tsuchiya K, Watanabe M, Kumanogoh A, Tsukita S, Takeda K
  • Journal Title: Mucosal Immunol. Volume: 10 Issue: 2 Pages: 446-459
  • DOI: 10.1038/mi.2016.58
  • Peer Reviewed
• [Journal Article] Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors. (2017)
  • Author(s): Nakata T, Shimizu H, Nagata S, Ito G, Fujii S, Suzuki K, Kawamoto A, Ishibashi F, Kuno R, Anzai S, Murano T, Mizutani T, Oshima S, Tsuchiya K, Nakamura T, Hozumi K, Watanabe M, Okamoto R
  • Journal Title: Biochem Biophys Res Commun. Volume: 482 Issue: 4 Pages: 1296-1303
  • DOI: 10.1016/j.bbrc.2016.12.031
  • Peer Reviewed / Open Access
• [Journal Article] CDX2 expression induced by leukocytapheresis might be associated with mucosal healing in ulcerative colitis. (2016)
  • Author(s): Tsuchiya K, Hayashi R, Fukushima K, Hibiya S, Horita N, Negi M, Itoh E, Akashi T, Eishi Y, Motoya S, Takeuchi Y, Kunisaki R, Fukunaga K, Nakamura S, Yoshimura N, Takazoe M, Iizuka B, Suzuki Y, Nagahori M, Watanabe M
  • Journal Title: J Gastoenterol Hepatol. Volume: 61 Issue: 5 Pages: 1032-1039
  • DOI: 10.1111/jgh.13645
  • Peer Reviewed
• [Journal Article] Data showing proliferation and differentiation of intestinal epithelial cells under targeted depletion of Notch ligands in mouse intestine. (2016)
  • Author(s): Nakata T, Shimizu H, Nagata S, Ito G, Fujii S, Suzuki K, Kawamoto A, Ishibashi F, Kuno R, Anzai S, Murano T, Mizutani T, Oshima S, Tsuchiya K, Nakamura T, Hozumi K, Watanabe M, Okamoto R
  • Journal Title: Data Brief. Volume: 10 Pages: 551-556
  • DOI: 10.1016/j.dib.2016.12.045
  • Peer Reviewed / Open Access
• [Journal Article] The ubiquitin hybrid gene UBA52 regulates ubiquitination of ribosome and sustains embryonic development. (2016)
  • Author(s): Kobayashi M, Oshima S, Maeyashiki C, Nibe Y, Otsubo K, Matsuzawa Y, Memoto Y, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Watanabe M
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 36780-36780
  • DOI: 10.1038/srep36780
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PGE2 is a direct and robust mediator of anion/fluid secretion by human intestinal epithelial cells. (2016)
  • Author(s): Fujii S, Okamoto R, Suzuki K, Kawamoto A, Ishibashi F, Nakata T, Murano T, Ito G, Shimizu H, Mizutani T, Oshima S, Tsuchiya K, Nakamura T, Araki A, Ohtsuka K, Watanabe M
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 36795-36795
  • DOI: 10.1038/srep36795
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Novel CD200 homologues iSEC1 and iSEC2 are gastrointestinal secretory cell-specific ligands of inhibitory receptor CD200R (2016)
  • Author(s): Kojima, T., Tsuchiya, K., Ikemizu, S., Yoshikawa, S., Yamanishi, Y., Watanabe, M., and Karasuyama, H.
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 36457-36457
  • DOI: 10.1038/srep36457
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Reduced human α-defensin 6 in non-inflamed jejunal tissue of Crohn’s disease patients (2016)
  • Author(s): Hayashi R , Tsuchiya K, Okamoto R,Watanabe M,et al
  • Journal Title: Inflammatory Bowel Diseases Volume: 22 Issue: 5 Pages: 1119-28
  • DOI: 10.1097/mib.0000000000000707
  • Peer Reviewed
• [Journal Article] Atonal homolog 1 protein stabilized by tumor necrosis factor α induces high malignant potential in colon cancer cell line. (2015)
  • Author(s): Keita Fukushima, Kiichiro Tsuchiya,Okamoto Ryuichi, Mamoru Watanabe,et al
  • Journal Title: Cancer Sci Volume: 106 Issue: 8 Pages: 1000-7
  • DOI: 10.1111/cas.12703
  • Peer Reviewed / Open Access
• [Journal Article] Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. (2015)
  • Author(s): Tsuchiya K
  • Journal Title: Front Gastrointest Res. Volume: 34 Pages: 1-8
  • DOI: 10.1159/000381380
  • ISBN: 9783318054736, 9783318054743
  • Peer Reviewed
• [Presentation] Necroptosis stimulation regulates SQSTM1/p62-LC3 complex formation and polyubiquitination (2018)
  • Author(s): Emi Aonuma, Yoichi Nibe, Hiroki Matsuda, Kana Otsubo, Chiaki Maeyashiki, Masanori Kobayashi, Yu Matsuzawa, Mamoru Watanabe, Shigeru Oshima
  • Organizer: Keystone Symposia - Ubiquitin Signaling
  • Int'l Joint Research
• [Presentation] K33-linked polyubiquitin is recruited by SQSTM1/p62 (2018)
  • Author(s): Hiroki Matsuda, Yoichi Nibe, Emi Aonuma, Kana Otsubo, Chiaki Maeyashiki, Masanori Kobayashi, Yu Matsuzawa, Shinichiro Nakada, Mamoru Watanabe and Shigeru Oshima
  • Organizer: Keystone Symposia - Ubiquitin Signaling
  • Int'l Joint Research
• [Presentation] Novel polyubiquitin imaging system, PolyUb-FC, visualized atypical polyubiquitin chain in living cells (2018)
  • Author(s): Yoichi Nibe, Hiroki Matsuda, Emi Aonuma, Kana Otsubo, Chiaki Maeyashiki, Masanori Kobayashi, Yu Matsuzawa, Shinichiro Nakada, Mamoru Watanabe, Shigeru Oshima
  • Organizer: Keystone Symposia - Ubiquitin Signaling
  • Int'l Joint Research
• [Presentation] Long-chain fatty acid regulates autophagy and polyubiquitination in intestinal epithelial cells (2018)
  • Author(s): Kana Otsubo, Chiaki Maeyashiki, Emi Aonuma, Hiroki Matsuda, Yoichi Nibe, Masanori Kobayashi, Yu Matsuzawa, Mamoru Watanabe, Shigeru Oshima
  • Organizer: Keystone Symposia - Ubiquitin Signaling
  • Int'l Joint Research
• [Presentation] Atoh1 protein stability in sporadic colon cancer and colitis-associated cancer (2017)
  • Author(s): Tsuchiya K
  • Organizer: BIT’s 10th Anniversary of Protein & Peptide Conference-2017
  • Place of Presentation: Hilton Fukuoka Sea Hawk（Japan）
  • Year and Date: 2017-03-22
  • Int'l Joint Research / Invited
• [Presentation] 消化管幹細胞研究の最前線. (2017)
  • Author(s): 土屋輝一郎
  • Organizer: 第13回日本消化管学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2017-03-17
  • Invited
• [Presentation] 炎症性腸疾患に付随するがんの病態解明 (2017)
  • Author(s): 土屋 輝一郎、渡辺 守
  • Organizer: JDDW2017
• [Presentation] Establishment of a colonic oranoid with Wnt-independent growth by long-term inflammatory stimulation. (2017)
  • Author(s): Shuji Hibiya, Kiichiro Tsuchiya, Mamoru Watanabe
  • Organizer: 第７６回日本癌学会学術総会
• [Presentation] TP53 mutation acquires higher malignant potential in human colon cancer cells (2017)
  • Author(s): Watanabe S, Tsuchiya K, Shirasaki T, Hibiya S, Oshima S, Nakamura T, Nishimura R, Okamoto R, Watanabe M.
  • Organizer: UEGW2017
  • Int'l Joint Research
• [Presentation] バルーン内視鏡生検検体を用いたクローン病病態解析. (2017)
  • Author(s): 土屋輝一郎、渡辺 守.
  • Organizer: 第35回サイトプロテクション研究会
  • Place of Presentation: メルパルク京都（京都府京都市）
• [Presentation] Atoh1 protein stabilization in colon tumor acquires the morphological change to signet ring cell carcinoma with cancer stem cell enrichment. (2016)
  • Author(s): Tsuchiya K, Hibiya S, Fukushima K, Shirasaki T, Oshima S, Okamoto R, Nakamura T, Watanabe M.
  • Organizer: APDW2016
  • Place of Presentation: Kobe convention center, KOBE（JAPAN）
  • Year and Date: 2016-11-03
  • Int'l Joint Research
• [Presentation] Construction of in vitro model of ulcerative colitis using mouse primary colonic organoid. (2016)
  • Author(s): Hibiya S, Tsuchiya K, Watanabe S, Shirasaki T, Oshima S, Okamoto R, Nakamura T, Watanabe M.
  • Organizer: UEGW2016
  • Place of Presentation: Vienna（Austria）
  • Year and Date: 2016-10-15
  • Int'l Joint Research
• [Presentation] Atoh1 protein stabilization in colon tumor acquires the phenotype of signet ring cell carcinoma with cancer stem cell enrichment. (2016)
  • Author(s): Kiichiro Tsuchiya, Shuji Hibiya, Keita Fukushima, Tomoaki Shirasaki, Shigeru Oshima, Ryuichi Okamoto, Tetsuya Nakamura, Mamoru Watanabe.
  • Organizer: AOCC2016
  • Place of Presentation: Kyoto International Conference Center, Kyoto（JAPAN）
  • Year and Date: 2016-07-08
  • Int'l Joint Research
• [Presentation] Mouse colonic organoid acquires wnt-independent survival property after long-term inflammation. (2016)
  • Author(s): Shuji Hibiya, Kiichiro Tsuchiya, Tomoaki Shirasaki, Keita Fukushima, Shigeru Oshima, Ryuichi Okamoto, Tetsuya Nakamura, Mamoru Watanabe.
  • Organizer: AOCC2016
  • Place of Presentation: Kyoto International Conference Center, Kyoto（JAPAN）
  • Year and Date: 2016-07-08
  • Int'l Joint Research
• [Presentation] Stimulation with the ligands of Toll like receptors in primary human organoids. (2016)
  • Author(s): Tomoaki Shirasaki, Kiichiro Tsuchiya, Shuji Hibiya, Ryu Nishimura, Keita Fukushima, Sho Watanabe, Ryuichi Okamoto, Tetsuya Nakamura and Mamoru Watanabe.
  • Organizer: AOCC2016
  • Place of Presentation: Kyoto International Conference Center, Kyoto（JAPAN）
  • Year and Date: 2016-07-08
  • Int'l Joint Research
• [Presentation] ATOH1 Protein stabillzation in tumor acquires the morphological change to signet ring cell enrichment in colon cancer. (2016)
  • Author(s): Kiichiro Tsuchiya, Shuji Hibiya, Keita Fukushima, Tomoaki Shirasaki, Ryuichi Okamoto, Tetsuya Nakamura, Mamoru Watanabe.
  • Organizer: DDW2016
  • Place of Presentation: San Diego（USA）
  • Year and Date: 2016-05-21
  • Int'l Joint Research
• [Presentation] Construction of in vitro model for inflammatory bowel disease using primary colonic organoid. (2016)
  • Author(s): Syuji Hibiya, Kiichiro Tsuchiya, Tomoaki Shirasaki, Keita Fukushima, Shigeru Oshima, Ryuichi Okamoto, Tetsuya Nakamura, Mamoru Watanabe.
  • Organizer: DDW2016
  • Place of Presentation: San Diego（USA）
  • Year and Date: 2016-05-21
  • Int'l Joint Research
• [Presentation] UBA52, ubiquitin hybrid ribisomal protein, regulates NF-κB signaling in colon cancer. (2016)
  • Author(s): Masanori Kobayashi, Shigeru Oshima, Yoishi Nibe, Chiaki Maeyashiki, Mamoru Watanabe.
  • Organizer: DDW2016
  • Place of Presentation: San Diego（USA）
  • Year and Date: 2016-05-21
  • Int'l Joint Research
• [Presentation] ヒトLgr5 発現可視化による粘液産生大腸癌ニッチ解析 (2016)
  • Author(s): 福島啓太、土屋輝一郎、加納嘉人、白崎友彬、日比谷秀爾、岡本隆一、中村哲也、渡辺 守.
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-04-21
• [Presentation] 長期炎症刺激による大腸上皮培養細胞の非可逆的NF κB シグナル活性. (2016)
  • Author(s): 日比谷秀爾、土屋輝一郎、白崎友彬、福島啓太、大島 茂、岡本隆一、中村哲也、渡辺 守.
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-04-21
• [Presentation] 小腸内視鏡生検検体を用いたクローン病におけるα defensin 発現解析. (2016)
  • Author(s): 林 亮平、土屋輝一郎、渡辺 守.
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-04-21
• [Presentation] 炎症関連大腸がんにおけるがん幹細胞形質獲得機構 (2016)
  • Author(s): 土屋 輝一郎
  • Organizer: 日本がん分子標的治療学会 第11回トランスレーショナルリサーチワークショップ
  • Place of Presentation: 都市センターホテル（東京都千代田区）
  • Year and Date: 2016-01-15
  • Invited
• [Presentation] 炎症性腸疾患関連大腸がんの形質獲得機構 (2016)
  • Author(s): 土屋輝一郎
  • Organizer: お茶の水がん学アカデミア１２４回集会
  • Place of Presentation: 順天堂大学（東京都文京区）
  • Invited
• [Presentation] 生検検体が切り拓くIBD病態解明と臨床展開. (2016)
  • Author(s): 土屋輝一郎
  • Organizer: 第14回 広島消化器免疫研究会
  • Place of Presentation: ホテルグランヴィア広島（広島県広島市）
  • Invited
• [Presentation] Mapping biopsy of entire small intestine revealed specific gene expression in Crohn’s disease (2015)
  • Author(s): Kiichiro Tsuchiya, Ryohei Hayashi, Shuji Hibiya, Keita Fukushima, Nobukatsu Horita, Tomoaki Shirasaki, Eriko Okada, Akihiro Araki, Kazuo Ohtsuka, Mamoru Watanabe
  • Organizer: UEG Week 2015
  • Place of Presentation: バルセロナ（スペイン）
  • Year and Date: 2015-10-24
  • Int'l Joint Research
• [Presentation] Acquisition of enhanced malignant potential in inflammation associated colon cancer (2015)
  • Author(s): Kiichiro Tsuchiya, Shuji Hibiya, Mamoru Watanabe
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] Mapping biopsy of entire small intestine is useful to assess the pathogenesis of Crohn’s disease. (2015)
  • Author(s): Kiichiro Tsuchiya, Ryohei Hayashi Mamoru Watanabe
  • Organizer: AOCC2015
  • Place of Presentation: 北京（中国）
  • Year and Date: 2015-06-18
  • Int'l Joint Research / Invited