Model mouse for malignant colorectal cancer progression

• Project/Area Number: 26430110
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kanazawa University
• Principal Investigator: Nakayama Mizuho 金沢大学, がん進展制御研究所, 助教 (20398225)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 大腸がん / マウスモデル / 転移 / 再発 / 悪性化 / p53 / 多段階発がんモデル

Outline of Final Research Achievements

p53 is highly mutated in colorectal cancer (CRC), however, the mechanisms of gain-of-function of mutant p53 in malignant progression have not yet been fully understood. We show that wild-type p53 inhibits nuclear accumulation of mutant p53（R270H）, however, relocalization of p53 to nuclei is associated with submucosal invasion and liver metastasis. Moreover, nuclear accumulation of mutant p53 (R270H) causes drastic morphological changes of organoids to complicated glandular architecture, which reflect poorly differentiated histology of in vivo tumors. Furthermore, mutant p53 (R270H) induces expression of wide range of genes through chromatin modification, which results in activation of Wnt/β-catenin pathways, which may be related to stemness and invasiveness. These results provide a novel mechanism of mutant p53 GOF in malignant progression of CRC.

Research Products

• [Journal Article] Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer. (2015)
  • Author(s): Oshima H, Nakayama M, Han TS, Naoi K, Ju X, Maeda Y, Robine S, Tsuchiya K, Sato T, Sato H, Taketo MM, Oshima M.
  • Journal Title: Cancer Res. Volume: 75 Issue: 4 Pages: 766-776
  • DOI: 10.1158/0008-5472.can-14-2036
  • NAID: 120005593962
  • Peer Reviewed / Open Access
• [Presentation] Novel model systems for colon cancer progression by accumulation of multiple driver mutations (2017)
  • Author(s): 中山 瑞穂、坂井絵梨、大島浩子、越前佳奈恵、藤井誠志、落合淳志、中山敬一、大島正伸
  • Organizer: 第76回日本癌学会
  • Place of Presentation: パシフィコ横浜 横浜市
  • Year and Date: 2017-09-28
  • Invited
• [Presentation] Nuclear localized mutant p53 causes invasion and metastasis by drastic morphological changes of colorectal tumor gland. (2016)
  • Author(s): 中山 瑞穂、坂井絵梨、越前佳奈恵、大島浩子、Tae-su Han、大木理恵子、落合淳志、Dominic C. Voon、武藤誠、大島正伸
  • Organizer: 第75回日本癌学会
  • Place of Presentation: パシフィコ横浜 横浜市
  • Year and Date: 2016-10-06
• [Presentation] 変異型p53による大腸がん浸潤とそのメカニズム (2015)
  • Author(s): 中山 瑞穂、坂井絵梨、大島浩子、武藤 誠、大島正伸
  • Organizer: 第74回がん学会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2015-10-08
• [Presentation] Mutant p53 increase invasive adenocarcinoma of intestinal tumors in Apc Δ716 mice. (2015)
  • Author(s): Mizuho Nakayama, Eri Sakai, Hiroko Oshima, Makoto M. Taketo, Masanobu Oshima
  • Organizer: The 10th International Symposium of the Institute Network "Towards the next generation research for cancer and Immunology"
  • Place of Presentation: 北海道札幌市 北海道大学
  • Year and Date: 2015-07-23
• [Presentation] p53 mutation induces malignant progression of intestinal tumors in Apc Δ716 mice (2015)
  • Author(s): Mizuho Nakayama, Hiroko Oshima, Eri Sakai, Makoto M. Taketo, Masanobu Oshima
  • Organizer: 日本がん学会シンポジウム／共同利用・共同研究拠点シンポジウム
  • Place of Presentation: 石川県金沢市
  • Year and Date: 2015-02-21 – 2015-02-22
• [Presentation] Progression to malignant adenocarcinoma of intestinal tumors by p53 mutation in Apc Δ716 mice. (2014)
  • Author(s): Mizuho Nakayama, Hiroko Oshima, Masanobu Oshima
  • Organizer: 第73回日本がん学会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Patent(Industrial Property Rights)] 特許権 (2017)
  • Inventor(s): 大島正伸、中山瑞穂、坂井絵梨
  • Industrial Property Rights Holder: 大島正伸、中山瑞穂、坂井絵梨
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-049202
  • Filing Date: 2017-03-14