Elucidation of pathogenic mechanism of internal radiation-induced thyroid cancer

• Project/Area Number: 16K00548
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Nagasaki University
• Principal Investigator: KURASHIGE Tomomi 長崎大学, 原爆後障害医療研究所, 助教 (60568955)
• Co-Investigator(Kenkyū-buntansha): 永山 雄二 長崎大学, 原爆後障害医療研究所, 教授 (30274632)
• Research Collaborator: SHIMAMURA Mika
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 放射線 / 甲状腺 / ROS / 発がん / オートファジー / DNA損傷 / 活性酸素種 / UV / RET/PTC / ジスルフィド結合 / 内部被ばく / 発癌

Outline of Final Research Achievements

To investigate the relationship between radiation-induced thyroid carcinogenesis and ROS, thyroid-specific autophagy deficient mice (Atg5-f/f;TPO-Cre mice), which were thought to sustainably produce much more ROS in the thyroid, were used. Atg5-f/f;TPO-Cre mice lack autophagy in a thyroid-specific manner from the embryonic stage. In the 12-months of age, accumulation of denatured protein was observed in the thyroid follicular epithelial cells of Atg5-f/f;TPO-Cre mice as compared with the control. In addition, oxidative damage (8-OHdG) and DNA double strand breaks (53BP1 foci) were also increased, which are thought to be caused by ROS from remaining undegraded defective mitochondria. These results demonstrated the relationship between sustained production of ROS and DNA damage in vivo.

Academic Significance and Societal Importance of the Research Achievements

我々は以前、甲状腺外部被ばくの際には被ばく時だけでなく被ばく後にも持続的で高いROS産生が起こり、この被ばく後のROSによりDNA損傷が誘発され一部が修復されず染色体の異常として残ることを明らかにした。
オートファジーの不全はROS産生を恒常的に亢進させDNA損傷を増加させることから、がんの形成や進展を加速させる可能性がある。今後、甲状腺特異的にオートファジー不全を起こしたマウスに放射線照射を行い甲状腺を経時的に解析することで細胞内のROS産生の増加が甲状腺の発がんに関与するかを解明することができる。さらにROSの関与が明らかになれば抗酸化剤の投与により放射線発がんを予防できる可能性がある。

Research Products

• [Journal Article] Intracellular redox status controls spherogenicity, an in vitro cancer stem cell marker, in thyroid cancer cell lines (2018)
  • Author(s): Shimamura Mika、Yamamoto Kazuo、Kurashige Tomomi、Nagayama Yuji
  • Journal Title: Experimental Cell Research Volume: 370 Issue: 2 Pages: 699-707
  • DOI: 10.1016/j.yexcr.2018.07.036
  • Peer Reviewed / Open Access
• [Journal Article] Mouse models of sporadic thyroid cancer derived from BRAFV600E alone or in combination with PTEN haploinsufficiency under physiologic TSH levels. (2018)
  • Author(s): Shimamura M, Shibusawa N, Kurashige T, Mussazhanova Z, Matsuzaki H, Nakashima M, Yamada M, Nagayama Y
  • Journal Title: PloS one Volume: 13 Issue: 8 Pages: e0201365-e0201365
  • DOI: 10.1371/journal.pone.0201365
  • NAID: 120006987838
  • Peer Reviewed / Open Access
• [Journal Article] N-Acetyl-L-cysteine protects thyroid cells against DNA damage induced by external and internal irradiation. (2017)
  • Author(s): Tomomi Kurashige, Mika Shimamura, Yuji Nagayama.
  • Journal Title: Radiation and Environmental Biophysics Volume: 56 Issue: 4 Pages: 405-412
  • DOI: 10.1007/s00411-017-0711-8
  • Peer Reviewed / Open Access
• [Presentation] Basal Autophagy Deficiency Causes Thyroid Follicular Epithelial Cell Death in Mice (2019)
  • Author(s): Yuji Nagayama, Tomomi Kurashige, Mika Shimamura, Mutsumi Matsuyama, Masahiro Nakashima.
  • Organizer: 第3回放射線災害・医科学研究拠点 国際シンポジウム
• [Presentation] マウス甲状腺におけるオートファジーの役割 (2018)
  • Author(s): 蔵重智美、松山睦美、中島正洋、嶋村美加、永山雄二
  • Organizer: 第3回放射線災害・医科学研究拠点カンファランス
• [Presentation] 甲状腺細胞における放射線誘導性DNA二重鎖切断に対する抗酸化剤の効果 (2016)
  • Author(s): 蔵重智美
  • Organizer: 第 1 回放射線災害・医科学研究拠点カンファランス
  • Place of Presentation: 長崎大学良順会館 (長崎県長崎市）