Elucidation of the role of MyD88 in Apc mutant intestinal tumor epithelial cells

• Project/Area Number: 18K07254
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: Kajino Rie 愛知県がんセンター(研究所), がん病態生理学分野, 研究員 (20633184)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Apc変異 / 大腸がん / 合成致死 / マウスモデル

Outline of Final Research Achievements

Mutations in the APC tumor suppressor gene are associated with the onset of adenoma carcinoma sequence in colorectal cancer. Conditional knockout of MyD88 in intestinal epithelial cells reduced the number of intestinal tumors in Apc mutant mice, genetically engineered mouse models of early colorectal cancer. Loss of MyD88 functions in Apc tumor cells resulted in the reduction of proliferation and caused apoptotic cell death. We found that epithelial MyD88 plays essential roles in the survival of the intestinal tumors, and that HIF-1a, NF-kB and Wnt pathways function downstream of MyD88. Further elucidation of the mechanism is expected to lead to the development of new treatments for colorectal cancer.

Academic Significance and Societal Importance of the Research Achievements

大腸がんはがんの中でも患者数が多く、本邦の部位別がん死亡率をみると大腸がんは男性で第３位、女性では第１位であり、効果的な治療法が必要とされている。本研究の成果は、APC変異を持つ大腸がん細胞ではMyD88がアキレス腱となりうることを示しており、MyD88やその下流の因子の働きを阻害する化合物が開発されて臨床で使用できるようになれば、APC変異を持つ多くの大腸がんに対する新しい治療戦略につながることが期待される。

Research Products

• [Journal Article] Synthetic lethality between MyD88 loss and mutations in Wnt/β-catenin pathway in intestinal tumor epithelial cells (2021)
  • Author(s): Rie Kajino-Sakamoto, Teruaki Fujishita, Makoto Mark Taketo, Masahiro Aoki
  • Journal Title: Oncogene Volume: 40 Issue: 2 Pages: 408-420
  • DOI: 10.1038/s41388-020-01541-3
  • Peer Reviewed
• [Presentation] Synthetic lethality between Apc mutation and MyD88 loss in intestinal tumor epithelial cells (2019)
  • Author(s): 梶野リエ、藤下晃章、武藤誠、青木正博
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Apc変異マウスの腸管腫瘍形成において腸上皮細胞のMyD88が果たす役割の解明 (2018)
  • Author(s): 梶野リエ、藤下晃章、武藤誠、青木正博
  • Organizer: 第77回日本癌学会学術総会
• [Remarks] 特定の遺伝子変異を持つ大腸がん細胞が生き残るのに重要な因子を発見
  • URL: https://www.pref.aichi.jp/cancer-center/cc/press/pdf/201112press_aoki.pdf