Mechanisms of Thyroid Cancer Development Affected by Polyoma Virus Infection

• Project/Area Number: 17K15662
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology
• Research Institution: Chiba University
• Principal Investigator: Yamaguchi Takashi 千葉大学, 大学院医学研究院, 講師 (60626563)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 甲状腺がん / 疾患動物モデル / 疾患モデルマウス / ポリオーマ属ウイルス / Large T抗原 / KrasG12D / 病理学 / 遺伝子 / 動物

Outline of Final Research Achievements

Poorly differentiated thyroid cancer is a disease with a poor prognosis and patients often have RAS-signaling abnormality. It has been suggested that polyoma virus infection might occur in the thyroid glands. The purpose of this study was to understand whether the RAS-signaling abnormality and polyoma virus infection work together in the development of thyroid cancer.
We constructed a genetically engineered mouse (GEM) model that expresses an oncogenic Kras mutation and SV40 tsA58, which is derived from a polyoma virus, large T antigen (TAg) in the thyroids of the GEM model. Forced activation of Ras-signaling and TAg expression resulted in poorly differentiated thyroid cancer in the GEM model. These results suggest that RAS-signaling abnormalities and polyoma virus infection might work together in the development of thyroid cancer.

Academic Significance and Societal Importance of the Research Achievements

甲状腺に発生する濾胞がんや分化度の低いがんは予後不良で、RASシグナルの変異を特徴とする。一方で甲状腺がんは、ポリオーマ属ウイルス感染との関係が指摘されてきたが、研究の開始以前、ポリオーマ属ウイルスSV40感染が、甲状腺がんの発生に寄与するとの直接的なエビデンスはなかった。また、活性化したRASシグナルとSV40ウイルスのLarge T抗原(TAg)が協働的に働いて、甲状腺上皮細胞の増殖を促すなどの背景メカニズムは不明であった。本研究では、マウス甲状腺に実際にRasの変異とTAgの発現を再現し、両現象が分化度の低い甲状腺がんの発症と進展を促進する証拠を獲得できた点で学術的・社会的に意義がある。