Analysis of the epithelial stem cell and the regenerative and carcinogenic mechanisms of digestive tract from the point of view of pSmad2/3L-Thr

• Project/Area Number: 25460938
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kansai Medical University
• Principal Investigator: FUKUI Toshiro 関西医科大学, 医学部, 講師 (60402905)
• Research Collaborator: KISHIMOTO Masanobu 関西医科大学, 医学部, 大学院生 ; TKAHASHI Yu 関西医科大学, 医学部, 大学院生 ; SUZUKI Ryo 関西医科大学, 医学部, 大学院生 ; UCHIDA Kazushige 関西医科大学, 医学部, 准教授 (40411516) ; NISHIO Akiyoshi 関西医科大学, 医学部, 准教授 (50362463) ; OKAZAKI Kazuichi 関西医科大学, 医学部, 教授 (70145126)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 消化管上皮幹細胞 / 粘膜再生 / 癌化 / マウスモデル / Smad / リン酸化 / 大腸癌 / 癌幹細胞 / 大腸炎関連大腸癌 / モデルマウス / pSmad3L-Ser / pSmad2/3L-Thr / 組織幹細胞 / 幹細胞 / 食道 / 小腸 / 大腸 / 大腸炎 / Smad蛋白

Outline of Final Research Achievements

In our previous study, we have identified significant expression of Smad2/3, phosphorylated at the specific linker threonine residues (pSmad2/3L-Thr), in murine gastric, small intestinal, and colon epithelial cells and have suggested these cells are their epithelial stem-like cells.
In this study, we have confirmed that pSmad2/3L-Thr can serve as a biomarker for esophageal stem cells. This investigation of Smad2/3 phosphorylation profiles have also clarified that additional carcinogenic pSmad3L-Ser signaling induced by chronic inflammation is an important early event in colitis-associated colorectal cancers.
Furthermore, this study has confirmed that pSmad2/3L-Thr can serve as a biomarker for cancer stem cells of a mouse model of colitis-associated colorectal cancer.

Research Products

• [Journal Article] Smad2/3 linker phosphorylation is a possible marker of cancer stem cells and correlates with carcinogenesis in a mouse model of colitis-associated colorectal cancer (2015)
  • Author(s): Ryo Suzuki
  • Journal Title: Journal of Crohn’s and Colitis Volume: 9 Issue: 7 Pages: 565-574
  • DOI: 10.1093/ecco-jcc/jjv073
  • Peer Reviewed
• [Journal Article] Phosphorylation of Smad2/3 at Specific Linker Threonine Indicates Slow-Cycling Intestinal Stem-Like Cells Before Reentry to Cell Cycle (2015)
  • Author(s): Kishimoto M, Fukui T, Suzuki R, Takahashi Y, Sumimoto K, Okazaki T, Sakao M, Sakaguchi Y, Yoshida K, Uchida K, Nishio A, Matsuzaki K, Okazaki K
  • Journal Title: Digestive Diseases and Sciences Volume: 60 Issue: 2 Pages: 362-374
  • DOI: 10.1007/s10620-014-3348-3
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylation of Smad2/3 at the specific linker threonine residue indicates slow-cycling esophageal stem-like cells before re-entry to the cell cycle (2014)
  • Author(s): Takahashi Y, Fukui T, Kishimoto M, Suzuki R, Mitsuyama T, Sumimoto K, Okazaki T, Sakao M, Sakaguchi Y, Yoshida K, Uchida K, Nishio A, Matsuzaki K, Okazaki K
  • Journal Title: Diseases of the Esophagus Volume: - Issue: 2 Pages: 107-115
  • DOI: 10.1111/dote.12277
  • Peer Reviewed / Open Access
• [Presentation] Carcinogenic and stem cell-like phenotypes of Smad2/3 linker phosphorylation in a mouse model of colitis-associated colorectal cancer. (2015)
  • Author(s): Toshiro Fukui, Ryo Suzuki, Masanobu Kishimoto, Yu Takahashi, Sachi Miyamoto, Kazushige Uchida, Akiyoshi Nishio, Kazuichi Okazaki
  • Organizer: APDW (Asian Pacific Digestive Week) 2015
  • Place of Presentation: Taipei International Convention Center, Taipei, Taiwan
  • Year and Date: 2015-12-03
  • Int'l Joint Research
• [Presentation] 小腸幹細胞様細胞マーカーとしてのpSmad2/3-L-Thrの可能性の検討 (2015)
  • Author(s): 福井寿朗 岸本真房 鈴木亮 高橋悠 宮本早知 松本泰司 谷村雄志 内田一茂 西尾彰功 岡崎和一
  • Organizer: 第53回小腸研究会
  • Place of Presentation: アイーナ（いわて県民情報交流センター）（岩手県・盛岡市）
  • Year and Date: 2015-11-07
• [Presentation] 特定のリンカー部スレオニンがリン酸化されたSmad2/3蛋白（pSmad2/3L-Thr）の消化管上皮幹細胞マーカーとしての検討と応用 (2015)
  • Author(s): 高橋悠 福井寿朗 岡崎和一
  • Organizer: 第103回日本消化器病学会近畿支部例会 ワークショップ2 次代を担う消化器研究 bench to bed
  • Place of Presentation: 大阪国際交流センター 大阪市
  • Year and Date: 2015-09-26
• [Presentation] Carcinogenic and stem cell-like phenotypes of Smad2/3 linker phosphorylation in a mouse model of colitis-associated colorectal cancer. (2015)
  • Author(s): Toshiro Fukui, Ryo Suzuki, Masanobu Kishimoto, Kazuichi Okazaki
  • Organizer: GI Research Academy 2015
  • Place of Presentation: ロイヤルパークホテル（東京）
  • Year and Date: 2015-06-12
• [Presentation] リンカー部スレオニンリン酸化smad2/3蛋白発現による腸管幹細胞マーカーの探索 (2013)
  • Author(s): 岸本真房 鈴木亮 高橋悠 福井寿朗 坂口雄沢 内田一茂 西尾彰功 岡崎和一
  • Organizer: 第50回日本臨床分子医学会学術集会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] Phosphorylation of Smad2/3 in Stem Cells of Small Intestine (2013)
  • Author(s): Yu Takahashi, Toshiro Fukui, Ryo Suzuki, Masanobu Kishimoto, Kazushige Uchida, Koichi Matsuzaki, Akiyoshi Nishio, Kazuichi Okazaki
  • Organizer: 21th United European Gastroenterology Week
  • Place of Presentation: Internationales Congress Centrum Berlin, Berlin, Germany