Study on the role of inflammation in gastrointestinal cancer and regeneration

• Project/Area Number: 15K21775
• Research Category: Fund for the Promotion of Joint International Research (Home-Returning Researcher Development Research)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Hokkaido University (2017, 2021-2022); Keio University (2015, 2018-2020)
• Principal Investigator: Taniguchi Koji 北海道大学, 医学研究院, 教授 (20627020)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥57,200,000 (Direct Cost: ¥44,000,000、Indirect Cost: ¥13,200,000)
• Keywords: 炎症 / がん / 組織再生 / 再生

Outline of Final Research Achievements

We found that the Src family-kinase (SFK)-YAP pathway is activated by deletion of the tumor suppressor gene adenomatous polyposis coli (APC) in colorectal cancer. Using a tissue microarray (TMA) of human colon cancer samples, we found co-activation of SFK, YAP, STAT3, and Notch signals in about 70% of the samples. We also confirmed the increased expression of gp130 in human colorectal cancer samples compared to normal colon samples. In addition, we revealed that co-administration of SFK inhibitor and JAK inhibitor is more effective than single-agent inhibition in the treatment of colorectal cancer. These data suggest the importance of the gp130-SFK-YAP pathway in colorectal cancer.

Academic Significance and Societal Importance of the Research Achievements

組織再生を促進するシグナルの多くは癌においても活性化している事が知られており、このシグナルが癌においても活性化していれば、癌の新しい治療標的になる可能性がある。今回の研究で、大腸がんにおいてもSrc family-kinase (SFK)-YAP経路が腫瘍抑制遺伝子 Adenomatous polyposis coli (APC)の欠損により誘導されることを明らかにしたので、このSFK-YAP経路が大腸がんにおけるがんの新規治療標的となる可能性がある。

Research Products

• [Int'l Joint Research] University of California, San Diego(米国)
• [Int'l Joint Research] University of California, San Diego(米国)
• [Int'l Joint Research] University of California, San Diego(米国)
• [Int'l Joint Research] University of California, San Diego(米国)
• [Int'l Joint Research] University of California, San Diego（米国）
• [Journal Article] NKG2D Ligand Expression Induced by Oxidative Stress Mitigates Cutaneous Ischemia-Reperfusion Injury (2023)
  • Author(s): Keishi Makita、Noriyuki Otsuka、Utano Tomaru、Koji Taniguchi、Masanori Kasahara
  • Journal Title: Journal of Histochemistry & Cytochemistry Volume: 71 Issue: 2 Pages: 61-72
  • DOI: 10.1369/00221554221147582
  • Peer Reviewed
• [Journal Article] Identification of Quiescent LGR5+ Stem Cells in the Human Colon (2022)
  • Author(s): Ishikawa K, Sugimoto S, Oda M, Fujii M, Toshimitsu K, Sawada K, Shimokawa M, Saito M, Kawasaki K, Ishii R, Taniguchi K, Sato T.
  • Journal Title: Gastroenterology. Volume: 163 Issue: 5 Pages: 1391-1406
  • DOI: 10.1053/j.gastro.2022.07.081
  • Peer Reviewed / Open Access
• [Journal Article] Inflammation-Induced Tumorigenesis and Metastasis (2021)
  • Author(s): Sana Hibino, Tetsuro Kawazoe, Hidenori Kasahara, Shinji Itoh, Takatsugu Ishimoto, Mamiko Sakata-Yanagimoto and Koji Taniguchi
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 11 Pages: 5421-5421
  • DOI: 10.3390/ijms22115421
  • Peer Reviewed / Open Access
• [Journal Article] Immunomodulation by Inflammation during Liver and Gastrointestinal Tumorigenesis and Aging (2021)
  • Author(s): Nao Nagai, Yotaro Kudo, Daisuke Aki, Hayato Nakagawa, Koji Taniguchi
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 5 Pages: 2238-2238
  • DOI: 10.3390/ijms22052238
  • Peer Reviewed / Open Access
• [Journal Article] Autocrine leukemia inhibitory factor promotes esophageal squamous cell carcinoma progression via Src family kinase-dependent Yes-associated protein activation (2020)
  • Author(s): Kawazoe T, Saeki H, Oki E, Oda Y, Maehara Y, Mori, M, Taniguchi K
  • Journal Title: Molecular Cancer Research Volume: 18 Issue: 12 Pages: 1876-1888
  • DOI: 10.1158/1541-7786.mcr-20-0186
  • Peer Reviewed / Open Access
• [Journal Article] Fructose stimulated de novo lipogenesis is promoted by inflammation (2020)
  • Author(s): Todoric J, Di CaroG, Reibe S, Henstridge D, Green C, Vrbanac A, Ceteci Fa, Conche C, McNulty R, Shalapour S, Taniguchi K, Meikle P, Watrous J, Moranchel R, Najhawan M, Jain M, Liu X, Kisseleva T, Diaz-Meco M, Moscat J, Knight R, Greten FR, Lau L Metallo C, Febbraio M, Karin M
  • Journal Title: Nature Metabolism Volume: 2 Issue: 10 Pages: 1034-1045
  • DOI: 10.1038/s42255-020-0261-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly (2020)
  • Author(s): He F, Antonucci L, Yamachika S, Zhang Z, Taniguchi K, Umemura A, Hatzivassiliou G, Roose-Girma M, Reina-Campos M, Duran A, Diaz-Meco MT, Moscat J, Sun B, Karin M
  • Journal Title: Journal of Hepatology Volume: 72 Issue: 6 Pages: 1182-1195
  • DOI: 10.1016/j.jhep.2020.01.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RIPK1 mediates TNF-induced intestinal crypt apoptosis during chronic NF-кB activation. (2020)
  • Author(s): Wong J, Garcia-Carbonell R, Zelic M, Ho SB, Boland BS, Yao S-J, Desai, SA, Das, S Planell N, Harris PA, Font-Burgada J, Taniguchi K, Bertin J, Salas A, Pasparakis M, Gough PJ, Kelliher M, Karin M, Guma M
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology. Volume: 9 Issue: 2 Pages: 295-312
  • DOI: 10.1016/j.jcmgh.2019.10.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Sprouty/Spred family as tumor suppressors: Coming of age (2019)
  • Author(s): Kawazoe Tetsuro、Taniguchi Koji
  • Journal Title: Cancer Science Volume: 110 Issue: 5 Pages: 1525-1535
  • DOI: 10.1111/cas.13999
  • Peer Reviewed / Open Access
• [Journal Article] NF-kB, inflammation, immunity and cancer : coming of age (2018)
  • Author(s): Taniguchi K, Karin M
  • Journal Title: Nat Rev Immunol Volume: 18 Issue: 5 Pages: 309-324
  • DOI: 10.1038/nri.2017.142
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Integrative genomic analysis of mouse and human hepatocellular carcinoma. (2018)
  • Author(s): Dow M, Pyke RM, Tsui BY, Alexandrov LB, Nakagawa H, Taniguchi K, Seki E, Harismendy O, Shalapour S, Karin M, Carter H, Font-Burgada J
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 115 Issue: 42
  • DOI: 10.1073/pnas.1811029115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis. (2017)
  • Author(s): Taniguchi K, Moroishi T, de Jong PR, Krawczyk M, Grebbin BM, Luo H, Xu RH, Golob-Schwarzl N, Schweiger C, Wang K, Di Caro G, Feng Y, Fearon ER, Raz E, Kenner L, Farin HF, Guan KL, Haybaeck J, Datz C, Zhang K, Karin M.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114 Issue: 7 Pages: 1643-1648
  • DOI: 10.1073/pnas.1620290114
  • Peer Reviewed / Int'l Joint Research
• [Presentation] New development in translational research targeting inflammation and immunity in colorectal cancer (2022)
  • Author(s): Koji Taniguchi
  • Organizer: 第81回日本癌学会学術総会
  • Int'l Joint Research / Invited
• [Presentation] 第60回日本癌治療学会学術集会 (2022)
  • Author(s): Koji Taniguchi
  • Organizer: New development in translational research targeting inflammation in colorectal cancer
  • Int'l Joint Research / Invited
• [Presentation] A gp130-SFK-YAP module promotes colonic tumorigenesis (2022)
  • Author(s): Koji Taniguchi
  • Organizer: 第33回日本消化器癌発生学会総会
• [Presentation] Study on the role of activation of the SFK-YAP signaling induced by IL-6 family cytokines in gastrointestinal cancer (2022)
  • Author(s): Koji Taniguchi
  • Organizer: 第45回日本分子生物学会年会
• [Presentation] 大腸がんの炎症・免疫を標的とした治療開発 (2021)
  • Author(s): 谷口 浩二
  • Organizer: 第80回日本癌学会学術総会
  • Int'l Joint Research / Invited
• [Presentation] サイトカインで活性化されるSFK-YAPシグナルの消化器がんでの役割の検討 (2021)
  • Author(s): 谷口 浩二
  • Organizer: 第44回日本分子生物学会年会
  • Int'l Joint Research
• [Presentation] LIF-SFK-YAP経路はヒト食道扁平上皮がんの進展を促進する (2021)
  • Author(s): 谷口 浩二
  • Organizer: 第110回日本病理学会総会
  • Int'l Joint Research
• [Presentation] The role of IL-6 family cytokines in gastrointestinal cancer (2020)
  • Author(s): Koji Taniguchi, Tetsuro Kawazoe
  • Organizer: AACR Annual Meeting 2020
  • Int'l Joint Research
• [Presentation] Autocrine LIF signaling promotes the progression of human esophageal squamous cell carcinoma (2020)
  • Author(s): 谷口 浩二、川副 徹郎
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] The SFK-YAP axis can be a new potential therapeutic target in colorectal cancer (2020)
  • Author(s): 谷口 浩二
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Development of novel treatment for esophageal squamous cell carcinoma targeting inflammatory transduction pathway (2020)
  • Author(s): 川副 徹郎、谷口 浩二
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] がん細胞における代謝変動とその機能的役割 (2019)
  • Author(s): 谷口 浩二
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] The SFK-YAP pathway is a new potential therapeutic target in colorectal cancer. (2019)
  • Author(s): 谷口 浩二
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Functional analysis of autocrine LIF signaling in esophageal squamous cell carcinoma (2019)
  • Author(s): 谷口 浩二、川副 徹郎
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] A gp130-Src-YAP module links inflammation to regeneration and cancer. (2019)
  • Author(s): 谷口 浩二
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Development of novel treatment strategy for esophageal squamous cell carcinoma targeting inflammatory transduction pathway. (2019)
  • Author(s): 川副 徹郎、佐伯 浩司、沖 英次、小田 義直、森 正樹、谷口 浩二
  • Organizer: 第57回日本癌治療学会学術総会
• [Presentation] 食道扁平上皮癌における炎症シグナル伝達経路阻害による治療の基礎的検討 (2019)
  • Author(s): 川副 徹郎、佐伯 浩司、中島雄一郎、沖 英次、小田 義直、谷口 浩二
  • Organizer: 第119回日本外科学会定期学術集会
• [Presentation] A Src-YAP module promotes colonic tumorigenesis. (2018)
  • Author(s): 谷口 浩二
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] A Src-YAP module is a new potential therapeutic target in colorectal cancer. (2018)
  • Author(s): 谷口 浩二
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] A gp130-Src-YAP module links inflammation to regeneration and cancer (2018)
  • Author(s): 谷口 浩二
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] SFK-YAPモジュールは炎症と組織再生・がんをリンクする (2018)
  • Author(s): 谷口 浩二
  • Organizer: 「先進ゲノム支援」拡大班会議
• [Presentation] Inhibition of the Src-YAP pathway is a candidate therapeutic target in esophageal squamous cell carcinoma (2018)
  • Author(s): 川副 徹郎、佐伯 浩司、沖 英次、小田 義直、谷口 浩二
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] The IL-6 family of cytokines regulates intestinal homeostasis and regeneration (2017)
  • Author(s): 谷口 浩二
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] The role of IL-6 family cytokines in intestinal homeostasis and regeneration (2017)
  • Author(s): 谷口 浩二、吉村 昭彦
  • Organizer: 第5回国際サイトカイン・インターフェロン学会年会2017
  • Int'l Joint Research
• [Presentation] The role of the cytokine receptor gp 130 during intestinal regeneration (2017)
  • Author(s): 谷口 浩二、吉村 昭彦
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] A gp130-Src-YAP module links inflammation to regeneration and cancer (2017)
  • Author(s): 谷口 浩二
  • Organizer: 第46回日本免疫学会学術集会
• [Book] Holland-Frei Cancer Medicine, 9th Edition (2017)
  • Author(s): Todoric J, Umemura A, Taniguchi K, Karin M
  • Total Pages: 7
  • Publisher: WILEY Blackwell