Study of tight junction regulators for colorectal tumor prevention

• Project/Area Number: 19K08388
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Masayoshi Fukuda 東京医科歯科大学, 東京医科歯科大学病院, 助教 (00733627)
• Co-Investigator(Kenkyū-buntansha): 渡辺 守 東京医科歯科大学, 高等研究院, 特別栄誉教授 (10175127) ; 鬼澤 道夫 福島県立医科大学, 医学部, 助教 (30783352) ; 永石 宇司 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座准教授 (60447464)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 大腸癌 / 大腸腫瘍

Outline of Research at the Start

本邦の大腸癌罹患者数は過去50年で急増し、その予防法・新規化学療法が求められている。隣りあった大腸上皮細胞はタイトジャンクションにより互いに結合しているが、癌化に伴ってタイトジャンクション関連タンパクの発現は変化し、癌細胞の転移や細胞増殖、癌微小環境の形成に関与することが示唆されてきた。本研究は、大腸癌発症におけるタイトジャンクションの役割を明らかにすることで、大腸癌予防及び治療法の基盤を提供することを目指す。

Outline of Final Research Achievements

The number of colorectal cancer patients has increased in Japan. It is difficult to establish an effective preventive method because mechanisms by which diet affects colorectal tumors are largely unknown. In the current study, effects of various amino acids on colon organoids and colon tumor organoids were screened. Their effects were subsequently analyzed in vivo. The results of this research are expected to contribute to an establishment of an effective method to prevent colorectal cancer.

Academic Significance and Societal Importance of the Research Achievements

本邦における大腸癌罹患者数増加してきたが、食餌が大腸腫瘍に及ぼす機序の多くが不明であるため有効な予防法確立を困難にしている。本研究成果は大腸癌予防法の確立へ向けた基盤形成に寄与すると期待できる。

Research Products

• [Journal Article] Nickel particles are present in Crohn's disease tissue and exacerbate intestinal inflammation in IBD susceptible mice. (2022)
  • Author(s): Hiroki Matsuda, Yoichi Nibe-Shirakihara, Akiko Tamura, Emi Aonuma, Satoko Arakawa, Kana Otsubo, Yasuhiro Nemoto, Takashi Nagaishi, Kiichiro Tsuchiya, Shigeomi Shimizu, Averil Ma, Mamoru Watanabe, Motohiro Uo, Ryuichi Okamoto, Shigeru Oshima.
  • Journal Title: Biochemical and Biophysical Research Communications. Volume: 592 Pages: 74-80
  • DOI: 10.1016/j.bbrc.2021.12.111
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activated mucosal-associated invariant T cells have a pathogenic role in a murine model of inflammatory bowel disease. (2022)
  • Author(s): usuke Yasutomi, Asako Chiba, Keiichi Haga, Goh Murayama, Ayako Makiyama, Taiga Kuga, Mamoru Watanabe, Ryuichi Okamoto, Akihito Nagahara, Takashi Nagaishi, Saichiko Miyake.
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology. Volume: 13 Issue: 1 Pages: 81-93
  • DOI: 10.1016/j.jcmgh.2021.08.018
  • Peer Reviewed / Open Access
• [Journal Article] 腸内細菌叢に対するIgAの重要性. (2022)
  • Author(s): 永石宇司.
  • Journal Title: 日本臨床腸内微生物学会誌. Volume: 24 Pages: 19-20
• [Journal Article] 【こんなときどうする】大腸 診断 回盲弁を越えられない (2021)
  • Author(s): 福田将義
  • Journal Title: 消化器内視鏡 Volume: 34 Pages: 416-417
• [Journal Article] らくわかり!消化器内視鏡のCOVID-19感染対策 最新マニュアル 全国施設のオリジナルグッズも紹介!】シチュエーション別でわかる内視鏡室の感染対策 内視鏡室全体の感染対策・スタッフ配置 (2021)
  • Author(s): 福田将義
  • Journal Title: 消化器ナーシング Volume: 26 Pages: 718-723
  • Open Access
• [Journal Article] Immunoglobulin A-specific deficiency induces spontaneous inflammation specifically in the ileum (2021)
  • Author(s): Nagaishi Takashi、Watabe Taro、Kotake Kunihiko、Kumazawa Toshihiko、Aida Tomomi、et al.
  • Journal Title: Gut Volume: 71 Issue: 3 Pages: 487-496
  • DOI: 10.1136/gutjnl-2020-322873
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A potent endocytosis inhibitor Ikarugamycin up-regulates TNF production. (2021)
  • Author(s): Ai Minamidate, Michio Onizawa, Chikako Saito, Rie Hikichi, Tomoaki Mochimaru, Mai Murakami, Chiharu Sakuma, Takehito Asakawa, Yuichi Hiraoka, Shigeru Oshima, Takashi Nagaishi, Kiichiro Tsuchiya, Hiromasa Ohira, Ryuichi Okamoto, Mamoru Watanabe.
  • Journal Title: Biochemistry and Biophysics Reports. Volume: 27 Pages: 101065-101065
  • DOI: 10.1016/j.bbrep.2021.101065
  • Peer Reviewed / Open Access
• [Journal Article] Oral administration of D-serine prevents the onset and progression of colitis in mice. (2021)
  • Author(s): Takehito Asakawa, Michio Onizawa, Chikako Saito, Rie Hikichi, Daiki Yamada, Ai Minamidate, Tomoaki Mochimaru, Shun-ichiro Asahara, Yoshiaki Kido, Shigeru Oshima, Takashi Nagaishi, Kiichiro Tsuchiya, Hiromasa Ohira, Ryuichi Okamoto, Mamoru Watanabe.
  • Journal Title: Journal of Gastroenterolog. Volume: 56 Issue: 8 Pages: 732-745
  • DOI: 10.1007/s00535-021-01792-1
  • Peer Reviewed / Open Access
• [Journal Article] 免疫グロブリンAの欠損により回腸特異的な炎症が自然発症する. (2021)
  • Author(s): 安達貴弘，永石宇司.
  • Journal Title: 消化器学サイエンス. Volume: 5 Pages: 230-232
• [Journal Article] Intraepithelial Lymphocytes Suppress Intestinal Tumor Growth by Cell-to-Cell Contact via CD103/E-Cadherin Signal. (2021)
  • Author(s): Ryo Morikawa, Yasuhiro Nemoto, Yuki Yonemoto, Shohei Tanaka, Yuria Takei, Shigeru Oshima, Takashi Nagaishi, Kiichiro Tsuchiya, Kengo Nozaki , Tomohiro Mizutani, Tetsuya Nakamura, Mamoru Watanabe, Ryuichi Okamoto.
  • Journal Title: Cell Mol Gastroenterol Hepatol. Volume: 11 Issue: 5 Pages: 1483-1503
  • DOI: 10.1016/j.jcmgh.2021.01.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nickel ions attenuate autophagy flux and induce transglutaminase 2 (TG2) mediated post-translational modification of SQSTM1/p62. (2020)
  • Author(s): Emi Aonuma, Akiko Tamura, Hiroki Matsuda, Takehito Asakawa, Yuriko Sakamaki, Kana Otsubo, Yoichi Nibe, Michio Onizawa, Yasuhiro Nemoto, Takashi Nagaishi, Kiichiro Tsuchiya, Tetsuya Nakamura, Motohiro Uo, Mamoru Watanabe, Ryuichi Okamoto, Shigeru Oshima.
  • Journal Title: Biochem Biophys Res Commun. Volume: 542 Pages: 17-23
  • DOI: 10.1016/j.bbrc.2021.01.023
  • Peer Reviewed / Open Access
• [Journal Article] CEACAM1 specifically suppresses B cell receptor signaling-mediated activation.. (2020)
  • Author(s): Naoya Tsugawa, Daiki Yamada, Taro Watabe, Michio Onizawa, Shuang Wang, Yasuhiro Nemoto, Shigeru Oshima, Takeshi Tsubata, Takahiro Adachi, Yohei Kawano, Mamoru Watanabe, Richard S. Blumberg, Ryuichi Okamoto, Takashi Nagaishi.
  • Journal Title: Biochem Biophys Res Commun. Volume: 535 Pages: 99-105
  • DOI: 10.1016/j.bbrc.2020.11.126
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Receptor-Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells. (2020)
  • Author(s): Otsubo K, Maeyashiki C, Nibe Y, Tamura A, Aonuma E, Matsuda H, Kobayashi M, Onizawa M, Nemoto Y, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Torii S, Itakura E, Watanabe M, Oshima S.
  • Journal Title: FEBS letters Volume: 594 Issue: 10 Pages: 1586-1595
  • DOI: 10.1002/1873-3468.13748
  • Peer Reviewed / Open Access
• [Journal Article] CD8αα+ T cells show amoeboid shape and frequent morphological change in?vitro, and localize to small intestinal intraepithelial region in?vivo (2020)
  • Author(s): Takei Yuria、Nemoto Yasuhiro、Morikawa Ryo、Tanaka Shohei、Oshima Shigeru、Nagaishi Takashi、Okamoto Ryuichi、Tsuchiya Kiichiro、Nakamura Tetsuya、Watanabe Mamoru
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 523 Issue: 2 Pages: 328-335
  • DOI: 10.1016/j.bbrc.2019.12.021
  • Peer Reviewed / Open Access
• [Journal Article] High-fat diet-derived free fatty acids impair the intestinal immune system and increase sensitivity to intestinal epithelial damage (2020)
  • Author(s): Tanaka Shohei、Nemoto Yasuhiro、Takei Yuria、Morikawa Ryo、Oshima Shigeru、Nagaishi Takashi、Okamoto Ryuichi、Tsuchiya Kiichiro、Nakamura Tetsuya、Stutte Susanne、Watanabe Mamoru
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 522 Issue: 4 Pages: 971-977
  • DOI: 10.1016/j.bbrc.2019.11.158
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Indolent T cell lymphoproliferative disorder with villous atrophy in small intestinediagnosed by single-balloon enteroscopy. (2019)
  • Author(s): Takashi Nagaishi, Daiki Yamada, Kohei Suzuki, Ryosuke Fukuyo, Eiko Saito, Masayoshi Fukuda, Taro Watabe, Naoya Tsugawa, Kengo Takeuchi, Kouhei Yamamoto, Ayako Arai, Kazuo Ohtsuka, Mamoru Watanabe
  • Journal Title: Clin J Gastroenterol. Volume: in press Issue: 5 Pages: 434-440
  • DOI: 10.1007/s12328-019-00971-1
  • Peer Reviewed / Open Access
• [Presentation] 潰瘍性大腸炎罹患粘膜に発生した腫瘍に対するESDの検討 (2021)
  • Author(s): 福田将義、大塚和朗、岡本隆一
  • Organizer: 第107回日本消化器病学会総会
• [Presentation] Colorectal ESD for neoplastic lesions on colitis mucosa (2021)
  • Author(s): 福田将義、大塚和朗、岡本隆一
  • Organizer: 第101回日本消化器内視鏡学会総会
• [Presentation] 潰瘍性大腸炎罹患粘膜に発生した腫瘍性病変に対する内視鏡治療戦略 (2021)
  • Author(s): 福田将義、大塚和朗、岡本隆一
  • Organizer: 第29回日本消化器関連学会週間
• [Presentation] The Lack of IgA spontaneously induces the inflammation only in the ileum. (2021)
  • Author(s): Daiki Yamada, Takahiro Adachi, Richard S. Blumberg, Ryuichi Okamoto, Takashi Nagaishi.
  • Organizer: The 50th Annual meeting of Japanese Society of Immunology
  • Int'l Joint Research
• [Presentation] A case of indolent T cell lymphoproliferative disorder of gastrointestinal tract with CCR4+ T cell infiltration. (2021)
  • Author(s): Daiki Yamada, Takashi Nagaishi, Eiko Saito, Masayoshi Fukuda, Ayako Arai, Ryuichi Okamoto.
  • Organizer: The 80th Annual meeting of Japanese Cancer Association
  • Int'l Joint Research
• [Presentation] BCR signaling-mediated activation in lymphoid tissues is regulated by the long isoform of CEACAM1. (2021)
  • Author(s): Takashi Nagaishi, Naoya Tsugawa, Daiki Yamada, Mamoru Watanabe, Richard S. Blumberg, Ryuichi Okamoto.
  • Organizer: Annual meeting of American Gastroenterology Association, Digestive Disease Week
  • Int'l Joint Research
• [Presentation] 腸内細菌叢に対するIgAの重要性. (2021)
  • Author(s): 永石宇司.
  • Organizer: 第24回日本臨床腸内微生物学会総会学術集会
  • Invited
• [Presentation] BCR-mediated activation in lymphoid tissues is regulated by Ceacam1. (2021)
  • Author(s): Takashi Nagaishi
  • Organizer: SMI Virtual Poster Hall
  • Int'l Joint Research / Invited
• [Presentation] 潰瘍性大腸炎罹患粘膜に発生した腫瘍性病変に対するESD の検討 (2020)
  • Author(s): 福田将義、根木真理子、大塚和朗
  • Organizer: 第28回 日本消化器関連学会週間
• [Presentation] 小腸難治性疾患の診断と治療の新知見 クローン病のバルーン内視鏡による小腸粘膜治癒評価 (2020)
  • Author(s): 竹中 健人, 大塚 和朗, 鈴木 康平, 日比谷 秀爾, 河本 亜美, 清水 寛路, 本林 麻衣子, 福田 将義, 藤井 俊光, 齊藤 詠子, 長堀 正和, 土屋 輝一郎, 渡辺 守, 岡本 隆一
  • Organizer: 第58回日本小腸学会学術集会
• [Presentation] 遺伝子解析により確定された大量輸血後のE型急性肝炎の1例 (2020)
  • Author(s): 川西 真明, 河崎 翔, 田中 将平, 伊藤 剛, 北畑 富貴子, 水谷 知裕, 新田 沙由梨, 福田 将義, 村川 美也子, 油井 史郎, 根本 泰宏, 岡田 英理子, 大島 茂, 井津井 康浩, 中川 美奈, 土屋 輝一郎, 柿沼 晴, 東 正新, 朝比奈 靖浩, 岡本 隆一
  • Organizer: 第362回日本消化器病学会関東支部例会
• [Presentation] BCR signaling in lymphoid tissues regulated by the long isoform of Ceacam1. (2020)
  • Author(s): Takashi Nagaishi, Naoya Tsugawa, Daiki Yamada, Yudai Kojima, Michio Onizawa, Taro Watabe, Richard S. Blumberg, Mamoru Watanabe.
  • Organizer: FOCIS 2020
  • Int'l Joint Research
• [Presentation] 慢性大腸炎モデルにおけるAPLの発現解析. (2020)
  • Author(s): 山田大貴, 永石宇司, 津川直也, 小島裕大, 渡部太郎, 渡辺 守.
  • Organizer: 第48回日本臨床免疫学会総会
• [Presentation] A case of villous atrophy with CCR4+ T cell infiltration in the small intestine. (2020)
  • Author(s): Takashi Nagaishi, Daiki Yamada, Naoya Tsugawa, Taro Watabe, Eiko Saito, Masayoshi Fukuda, Ayako Arai, Kazuo Ohtsuka, Mamoru Watanabe.
  • Organizer: UEGW 2020
  • Int'l Joint Research
• [Presentation] BCR signaling in lymphoid tissues is regulated by the long isoform of Ceacam1. (2020)
  • Author(s): Takashi Nagaishi, Naoya Tsugawa, Daiki Yamada, Taro Watabe, Michio Onizawa, Yudai Kojima, Richard S. Blumberg, Mamoru Watanabe.
  • Organizer: MICS 2020
  • Int'l Joint Research
• [Presentation] B cell receptor signaling in lymphoid tissues may be regulated by CEACAM1. (2020)
  • Author(s): Takashi Nagaishi, Naoya Tsugawa, Daiki Yamada, Taro Watabe, Michio Onizawa, Mamoru Watanabe.
  • Organizer: European Crohn’s and Colitis Organization 2020
  • Int'l Joint Research
• [Presentation] IBDモデルにおける腸管二次リンパ組織の機能解析. (2020)
  • Author(s): 永石宇司、渡部太郎、渡辺 守.
  • Organizer: 日本応用酵素協会「全身性炎症疾患の病因・病態に関する研究助成」 第9回研究発表会
• [Presentation] IgA-deficiency causes spontaneous enteritis. (2019)
  • Author(s): Takahiro Adachi, Taro Watabe, Takashi Nagaishi, Mamoru Watanabe, Hajime Karasuyama, Soichiro Yoshikawa.
  • Organizer: 第48回日本免疫学会学術集会
  • Int'l Joint Research
• [Presentation] BCR signaling in the activated B cells may be regulated by the long isoform of Ceacam1. (2019)
  • Author(s): Naoya Tsugawa, Takashi Nagaishi, Daiki Yamada, Yudai Kojima, Taro Watabe, Shuang Wang, Michio Onizawa, Takahiro Adachi, Mamoru Watanabe.
  • Organizer: 第48回日本免疫学会学術集会
  • Int'l Joint Research
• [Presentation] 培養腸上皮幹細胞を用いた炎症性腸疾患に対する再生医療の開発. (2019)
  • Author(s): 岡本隆一、清水寛路、鈴木康平、高橋純一、川井麻央、平栗優衣、竹岡さや香、杉原ハディ優樹、永田紗矢香、竹中健人、齋藤詠子、福田将義、藤井俊光、長堀正和、油井史郎、土屋輝一郎、大塚和朗、渡辺 守
  • Organizer: 厚生労働科学研究費 難治性疾患政策研究事業 「難治性炎症性腸管障害に関する調査研究」令和元年度 第1回総会
• [Presentation] Analysis of ileocecal immune response in an animal model of colitis. (2019)
  • Author(s): Daiki Yamada, Takashi Nagaishi, Taro Watabe, Naoya Tsugawa, Yudai Kojima,Nisha Jose, Akinori Hosoya, Takahiro Adachi, Mamoru Watanabe.
  • Organizer: International Congress of Mucosal Immunology 2019
  • Int'l Joint Research
• [Presentation] Analysis of APL expression in an animal model of chronic colitis. (2019)
  • Author(s): Takashi Nagaishi, Yudai Kojima, Taro Watabe, Naoya Tsugawa, Daiki Yamada, Nisha Jose, Akinori Hosoya, Masahiro Suzuki, Michio Onizawa, Mamoru Watanabe.
  • Organizer: Federation of Clinical Immunology Societies 2019
  • Int'l Joint Research
• [Presentation] APL downregulation in an animal model of chronic colitis. (2019)
  • Author(s): Daiki Yamada, Takashi Nagaishi, Yudai Kojima, Taro Watabe, Naoya Tsugawa, Nisha Jose, Akinori Hosoya, Masahiro Suzuki, Michio Onizawa, Mamoru Watanabe.
  • Organizer: Asian Organization of Crohn’s and Colitis 2019
  • Int'l Joint Research
• [Presentation] 潰瘍性大腸炎罹患粘膜に発生した腫瘍性病変に対するESDの検討. (2019)
  • Author(s): 福田将義、永石宇司、根木真理子、大塚和朗、渡辺 守.
  • Organizer: 第108回日本消化器内視鏡学会関東支部例会
• [Presentation] 慢性大腸炎モデルのT細胞におけるAPLの発現抑制. (2019)
  • Author(s): 山田大貴、永石宇司、津川直也、小島裕大、渡部太郎、鈴木雅博、鬼沢道夫、細谷明徳、Jose, Nisha、渡辺 守.
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] APL expression is downregulated in an animal model of chronic colitis. (2019)
  • Author(s): Takashi Nagaishi, Yudai Kojima, Daiki Yamada, Taro Watabe, Naoya Tsugawa, Nisha Jose, Michio Onizawa, Mamoru Watanabe.
  • Organizer: European Crohn’s and Colitis Organization 2019
  • Int'l Joint Research
• [Presentation] 慢性大腸炎モデルにおけるAPL発現の解析. (2019)
  • Author(s): 山田大貴、永石宇司、小島裕大、渡部太郎、津川直也、細谷明徳、Jose, Nisha、鈴木雅博、鬼沢道夫、渡辺 守.
  • Organizer: 第15回日本消化管学会総会学術集会
• [Patent(Industrial Property Rights)] 炎症性腸疾患の治療方法およびそれに用いるための医薬組成物 (2020)
  • Inventor(s): 永石 宇司
  • Industrial Property Rights Holder: 永石 宇司
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-554239
  • Filing Date: 2020
  • Acquisition Date: 2020
• [Patent(Industrial Property Rights)] 炎症性腸疾患の治療方法およびそれに用いるための医薬組成物 (2019)
  • Inventor(s): 永石宇司
  • Industrial Property Rights Holder: 永石宇司
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019