Analysis of the molecular mechanism for the prognostic biomarker of adjuvant chemotherapy

• Project/Area Number: 18K07341
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Nippon Medical School (2020); National Cancer Center Japan (2018-2019)
• Principal Investigator: Miura Nami 日本医科大学, 先端医学研究所, 助教 (80636978)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: アクチニン－４ / バイオマーカー / タンパク質相互作用 / 翻訳後修飾 / 浸潤・転移 / アクチン / リン酸化 / アクチニンー4 / 表面プラズモン共鳴法 / 非小細胞肺がん / PPI阻害

Outline of Final Research Achievements

Actinin-4 (ACTN4), an actin-bundling protein previously identified by our laboratory, is closely associated with variety of cellular processes, including cell motility and cancer metastasis. In this study, we found that the three-dimensional structure of the actin-binding domains of two ACTN4 mutants differs from that of wild-type ACTN4 and that these changes are responsible for the biological characteristics of ACTN4-mediated diseases.
Using an in vitro kinase assay and mass spectrometry, we confirmed the tyrosine phosphorylation of ACTN4 by epidermal growth factor receptor (EGFR) directly. The mass spectroscopy sequence coverage of the ACTN4 peptide was 77.6%, and six new phosphorylation sites were identified.

Academic Significance and Societal Importance of the Research Achievements

本研究により、非小細胞肺がんにおける術後補助化学療法の効果予測バイオマーカーであるACTN4のアクチンフィラメントとの結合様式およびACTN4のリン酸化に対する新たな知見が得られた。この結果から、ACTN4の生物学的活性化機構の一部を明らかにすることができ、ACTN4に対するダイレクトな創薬やACTN4のリン酸化機構を介した創薬が期待される。また、様々ながん種類でACTN4の発現していることが報告されているため、非小細胞肺がんだけではなく他のがんの種類への治療への応用が期待される。

Research Products

• [Journal Article] Actinin-4 splice variant - a complementary diagnostic and prognostic marker of pancreatic neuroendocrine neoplasms (2020)
  • Author(s): Xu Xiaojun、Honda Kazufumi、Miura Nami、Hori Shutaro、Le Blanc Solange、Bergmann Frank、Gaida Matthias M.、Volkmar Michael、Schimmack Simon、Hackert Thilo、Strobel Oliver、Felix Klaus
  • Journal Title: Journal of Cancer Volume: 11 Issue: 8 Pages: 2318-2328
  • DOI: 10.7150/jca.37503
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Monitoring of cancer patients via next‐generation sequencing of patient‐derived circulating tumor cells and tumor DNA (2019)
  • Author(s): Onidani Kaoru、Shoji Hirokazu、Kakizaki Takahiko、Yoshimoto Seiichi、Okaya Shinobu、Miura Nami、Sekikawa Shoichi、Furuta Koh、Lim Chwee Teck、Shibahara Takahiko、Boku Narikazu、Kato Ken、Honda Kazufumi
  • Journal Title: Cancer Science Volume: 110 Issue: 8 Pages: 2590-2599
  • DOI: 10.1111/cas.14092
  • Peer Reviewed / Open Access
• [Journal Article] Measurement of copy number of ACTN4 to optimize the therapeutic strategy for locally advanced pancreatic cancer (2018)
  • Author(s): Shoji Hirokazu、Miura Nami、Ueno Hideki、Honda Kazufumi
  • Journal Title: Pancreatology Volume: 18 Issue: 6 Pages: 624-629
  • DOI: 10.1016/j.pan.2018.06.003
  • Peer Reviewed
• [Presentation] Functional analysis of the prognostic biomarkers actinin-4 and its splice variant (2019)
  • Author(s): Nami Miura, Hideki Yamaguchi, Kazufumi Honda
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Analysis of the epidermal growth factor-induced phosphorylation of actinin-4 involved in cancer metastasis (2018)
  • Author(s): Nami Miura, Kaoru Onidani, Kazufumi Honda
  • Organizer: 17th Human Proteome Organization World Congress
  • Int'l Joint Research
• [Remarks] 日本医科大学 先端医学研究所 生体機能制御学部門
  • URL: https://www.nmsbiomarker.com
• [Remarks] 国立がん研究センター研究所 早期診断バイオマーカー開発部門
  • URL: https://www.ncc.go.jp/jp/ri/department/biomarker_for_early_detection_of_cancer/index.html