Roles of Dio2 (deiodinase, iodothyronine, type II) in colorectal tumorigenesis

• Project/Area Number: 17K07191
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: Kojima Yasushi 愛知県がんセンター(研究所), がん病態生理学分野, 主任研究員 (30464217)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 大腸がん / 甲状腺 / DIO2 / 大腸 / 腫瘍血管 / 遺伝子改変動物 / がん微小環境

Outline of Final Research Achievements

The prohormone thyroxine (T4) in circulation is converted to bioactive T3 in peripheral organs by the enzyme DIO2 (deiodinase, iodothyronine, type II), a major regulator of local thyroid hormone levels. Expression of Dio2 is upregulated in intestinal polyps of Apc mice, a mouse model of familial adenomatous polyposis and early-stage sporadic CRC. Treatment with iopanoic acid, a deiodinase inhibitor, or chemical thyroidectomy suppresses tumor formation in Apc mice, accompanied by reduced tumor cell proliferation and angiogenesis. The Cancer Genome Atlas (TCGA) data indicates up-regulation of DIO2 in CRC clinical samples and a close association of its expression pattern with the stromal component, consistently with almost exclusive expression of DIO2 in the stroma of human CRC as revealed by in situ hybridization. Collectively, these data highlight biological roles of DIO2 in the CRC tumor microenvironment.

Academic Significance and Societal Importance of the Research Achievements

本研究では、甲状腺ホルモンの局所組織での活性化に重要な役割を果たすDIO2が腫瘍組織の間質で高発現して、腫瘍血管増生、腫瘍成長を促進することを見出した。欧米を中心とした疫学調査では、甲状腺疾患と大腸がん発生には、なんらかの関係があることが示唆されている。しかしながら、なぜ、甲状腺と大腸がんに関連性が発生するのかについては、謎とされている。本研究の成果は、その謎の解明に資する可能性がある。また今後のより詳しい解析が必要であるが、さまざまな腫瘍組織でDIO2が腫瘍血管の増生に重要な役割を果たしている可能性がある。

Research Products

• [Journal Article] Stromal iodothyronine deiodinase 2 ( DIO 2) promotes the growth of intestinal tumors in Apc Δ716 mutant mice (2019)
  • Author(s): Kojima Yasushi、Kondo Yuriko、Fujishita Teruaki、Mishiro‐Sato Emi、Kajino‐Sakamoto Rie、Taketo Makoto Mark、Aoki Masahiro
  • Journal Title: Cancer Science Volume: 110 Issue: 8 Pages: 2520-2528
  • DOI: 10.1111/cas.14100
  • Peer Reviewed / Open Access
• [Presentation] 腸管腫瘍形成におけるDio2（２型脱ヨード酵素）の生物学的役割 (2019)
  • Author(s): 小島 康
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Role of Dio2 (deiodinase, Iodothyronine, Type II) in colon tumorigenesis. (2018)
  • Author(s): Kojima, Y., Fujishita T., Mishiro E., Kajino R., Taketo, M.M. & Aoki M.
  • Organizer: The 77th Annual Meeting of the Japanese Cancer Association, Osaka