Characteristics of human cancers showing high-level centrosome amplification and their sensitivity to drugs targeting centrosome amplification

• Project/Area Number: 16K08709
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Shinmura Kazuya 浜松医科大学, 医学部, 准教授 (40321880)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 中心体数的異常 / 中心体過剰複製 / WDR62 / POLQ / DNA グリコシラーゼ / PLK4 / 中心体局在 / DNAグリコシラーゼ / STIL / MUTYH / 染色体コピー数異常 / 8-bromoguanine / 肺腺癌 / 予後 / 中心体 / がん / DNA修復

Outline of Final Research Achievements

The followings were revealed in this study: (1) Overexpression of WDR62, which is localized in centrosome and cytoplasm, is associated with a poor prognosis in patients with lung adenocarcinoma (LAC) and concurrent overexpression of WDR62 and TPX2, a WDR62-interacting protein that is also overexpressed in LAC, induced centrosome amplification via AURKA activation in lung cells. 　(2) Overexpression of POLQ, one of translesion DNA synthesis polymerase, is associated with advanced pathologic stage, increased somatic mutation load, and PLK4 overexpression, the last inducing centrosome amplification, in LAC, suggesting that POLQ overexpression is involved in the pathogenesis of LAC. 　(3) Overexpression of centrosomal protein STIL in lung cancer is associated with high-level abnormality in chromosomal copy number, suggesting the induction of chromosomal numerical abnormality resulting from centrosome amplification due to STIL overexpression in lung cancer.

Academic Significance and Societal Importance of the Research Achievements

癌における中心体過剰複製を起こす要因や機構、および、中心体過剰複製と関連する癌形質に関する理解が深まった。将来的な癌治療戦略に貢献でき、国民の福祉向上につながる可能性があるものと思われる。

Research Products

• [Journal Article] Defective repair capacity of variant proteins of the DNA glycosylase NTHL1 for 5-hydroxyuracil, an oxidation product of cytosine (2019)
  • Author(s): Shinmura K, Kato H, Kawanishi Y, Goto M, Tao H, Yoshimura K, Nakamura S, Misawa K, Sugimura H
  • Journal Title: Free Radic Biol Med Volume: 131 Pages: 264-273
  • DOI: 10.1016/j.freeradbiomed.2018.12.010
  • Peer Reviewed
• [Journal Article] Mutation Spectrum Induced by 8-Bromoguanine, a Base Damaged by Reactive Brominating Species, in Human Cells (2017)
  • Author(s): Shinmura Kazuya、Kato Hisami、Goto Masanori、Tao Hong、Inoue Yusuke、Nakamura Satoki、Yoshida Haruki、Tsuzaki Emi、Sugimura Haruhiko
  • Journal Title: Oxidative Medicine and Cellular Longevity Volume: 2017 Issue: 1 Pages: 1-11
  • DOI: 10.1155/2017/7308501
  • Peer Reviewed
• [Journal Article] WDR62 overexpression is associated with a poor prognosis in patients with lung adenocarcinoma. (2017)
  • Author(s): Shinmura K, Kato H, Kawanishi Y, Igarashi H, Inoue Y, Yoshimura K, Nakamura S, Fujita H, Funai K, Tanahashi M, Niwa H, Ogawa H, Sugimura H
  • Journal Title: Mol Carcinog Volume: 印刷中 Issue: 8 Pages: 1984-1991
  • DOI: 10.1002/mc.22647
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Reduced expression of the DNA glycosylase gene MUTYH is associated with an increased number of somatic mutations via a reduction in the DNA repair capacity in prostate adenocarcinoma. (2017)
  • Author(s): Shinmura K, Kato H, Kawanishi Y, Yoshimura K, Igarashi H, Goto M, Tao H, Inoue Y, Sugiyama T, Furuse H, Ozono S, Sugimura H
  • Journal Title: Mol Carcinog Volume: 56(2) Issue: 2 Pages: 781-788
  • DOI: 10.1002/mc.22509
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] WDR62過剰発現は肺腺癌患者の予後不良因子となり、また、肺癌細胞の悪性度を増す (2017)
  • Author(s): 新村和也, 加藤寿美, 川西祐一, 五十嵐久喜, 井上裕介, 船井和仁, 棚橋雅幸, 丹羽宏, 小川博, 椙村春彦
  • Organizer: 第106回日本病理学会総会