The high-throughput screening to identify signaling pathways that are correlated with radioresistance of thyroid cancer stem cells

• Project/Area Number: 25861110
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Radiation science
• Research Institution: Nagasaki University
• Principal Investigator: MATSUSE Michiko 長崎大学, 原爆後障害医療研究所, 助教 (30533905)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 甲状腺癌 / 放射線 / 甲状腺 / 癌幹細胞

Outline of Final Research Achievements

There is accumulating evidence that solid tumor contain cancer stem cells (CSC), which play important roles in cancer initiation, progression, recurrence and metastasis. In thyroid cancer (TC), anaplastic thyroid cancer (ATC) is highly aggressive and resistant to conventional chemo/radio-therapy. Although it is considered that these properties are associated with CSC population in TC, little is known about their characteristics. In this study, we conducted high-throughput screening using siRNA for 714 kinases with ATC cell lines to identify signaling pathways that are correlated with their sphere-forming ability, which is one of hallmarks of CSCs. The siRNAs for PDGFRβ, JAK3 and PIM1/3 markedly inhibited sphere formation. We also demonstrated that siRNA for STAT3/5 and inhibitors for JAK and NF-κB similarly suppressed the sphere-forming ability after irradiation. These data suggest that the JAK-STAT-NF-κB signaling pathway is critical for survival and radioresistance of TC-CSCs.

Research Products

• [Journal Article] Targeted Foxe1 overexpression in mouse thyroid causes the development of multinodular goiter but does not promote carcinogenesis. (2016)
  • Author(s): Nikitski A, Saenko V, Shimamura M, Nakashima M, Matsuse M, Suzuki K, Rogounovitch T, Bogdanova T, Shibusawa N, Yamada M, Nagayama Y, Yamashita S, Mitsutake N.
  • Journal Title: Endocrinology Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] BRAFV600E mutation is highly prevalent in thyroid carcinomas in the young population in Fukushima: a different oncogenic profile from Chernobyl. (2015)
  • Author(s): Mitsutake N, Fukushima T, Matsuse M, Rogounovitch T, Saenko V, Uchino S, Ito M, Suzuki K, Suzuki S, Yamashita S
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 16976-16976
  • DOI: 10.1038/srep16976
  • NAID: 120006986823
  • Peer Reviewed / Open Access
• [Journal Article] TCUKIN and CORGI Consortiums, Carmona LG; JTCMS Consortium: The 8q24 rs6983267G variant is associated with increased thyroid cancer risk. (2015)
  • Author(s): Sahasrabudhe R, Estrada A, Lott P, Martin L, Polanco Echeverry G, Velez A, Neta G, Takahasi M, Saenko V, Mitsutake N, Jaeguer E, Duque CS, Rios A, Bohorquez M, Prieto R, Criollo A, Echeverry M, Tomlinson I
  • Journal Title: Endocr Relat Cancer Volume: 22 Issue: 5 Pages: 841-849
  • DOI: 10.1530/erc-15-0081
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The common genetic variant rs944289 on chromosome 14q13.3 associates with risk of both malignant and benign thyroid tumors in the Japanese population. (2015)
  • Author(s): Rogounovitch TI, Bychkov A, Takahashi M, Mitsutake N, Nakashima M, Nikitski AV, Hayashi T, Hirokawa M, Ishigaki K, Shigematsu K, Bogdanova T, Matsuse M, Nishihara E, Minami S, Yamanouchi K, Ito M, Kawaguchi T, Kondo H, Takamura N, Ito Y, Miyauchi A, Matsuda F, Yamashita S, Saenko VA.
  • Journal Title: Thyroid Volume: 25 Issue: 3 Pages: 333-340
  • DOI: 10.1089/thy.2014.0431
  • NAID: 120006987147
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Analysis of multiple markers for cancer stem-like cells in human thyroid carcinoma cell lines. (2014)
  • Author(s): Shimamura M, Nagayama Y, Matsuse M, Yamashita S, Mitsutake N.
  • Journal Title: Endocrine journal Volume: 61 Pages: 481-90
  • NAID: 130004443968
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Thyrotropin signaling confers more aggressive features with higher genomic instability on BRAFV600E-induced thyroid tumors in a mouse model. (2014)
  • Author(s): Orim F, Bychkov A, Shimamura M, Nakashima M, Ito M, Matsuse M, Kurashige T, Suzuki K, Saenko V, Nagayama Y, Yamashita S, Mitsutake N
  • Journal Title: Thyroid Volume: 24(3) Issue: 3 Pages: 502-510
  • DOI: 10.1089/thy.2013.0038
  • NAID: 120006986647
  • Peer Reviewed
• [Journal Article] Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease (2013)
  • Author(s): Landa I, Ganly I, Chan TA, Mitsutake N, Matsuse M, Ibrahimpasic T, Ghossein RA, Fagin JA
  • Journal Title: J Clin Endocrinol Metab Volume: 98 Issue: 9 Pages: E1562-E1566
  • DOI: 10.1210/jc.2013-2383
  • Peer Reviewed
• [Presentation] BRAF及びTERTプロモーター変異と甲状腺乳頭癌の悪性度との関連 (2015)
  • Author(s): 松瀬美智子、薮田智範、江本大紀、Vladimir Saenko、西原永潤、廣川満良、宮内昭、光武範吏、山下俊一
  • Organizer: 第58回日本甲状腺学会学術集会
  • Place of Presentation: 福島県文化センター （福島県 福島市）
  • Year and Date: 2015-11-05
• [Presentation] 三次元培養法を用いた新たな甲状腺初代培養法の開発 (2014)
  • Author(s): 松瀬美智子
  • Organizer: 第57回 日本甲状腺学会学術集会
  • Place of Presentation: ナレッジキャピタル コングレコンベンションセンター（大阪）
  • Year and Date: 2014-11-14