Classification of extracellular miRNAs by function and routes of their secretion

• Project/Area Number: 18K19489
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: National Cancer Center Japan
• Principal Investigator: Tsuchiya Naoto 国立研究開発法人国立がん研究センター, 研究所, ユニット長 (30322712)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 細胞外miRNA / 細胞外小胞 / miRNA / カタログ化 / 細胞外分泌 / 機能分類

Outline of Final Research Achievements

Extracellular vesicles are regulators of miRNA-mediated intercellular communications to maintain malignant properties of cancer cells. However, detailed mechanisms of how specific miRNAs selected and secreted from cancer cells are not fully understood. We aimed to understand the mechanism of miRNA secretion and to classify extracellular miRNAs by their functions. We found secretion of a similar subset of miRNAs from sarcoma cells. Two of them were found to induce the differentiation of monocyte to macrophage. Protein X was suggested to be secreted as vesicles (or complexes), which are distinct from exosomes. The RNA processing proteins and specific miRNAs were enriched in the protein X fraction. Secretion of these miRNAs were not affected by an exosome inhibitor. Screening intracellular molecules indicated the binding of the protein X with Exportins and RAB family proteins. These results suggest that the protein X is regulator for the intracellular protein and miRNA trafficking.

Academic Significance and Societal Importance of the Research Achievements

細胞外へと分泌されるmiRNAの機能が様々なヒト疾患の病態誘発に重要な役割を有することは疑いない事実であるが、分泌機能の詳細とそれらの機能、特に腫瘍微小環境中に存在する非腫瘍細胞への影響は不明な点が多い。本研究の成果は、疾患誘発の分子機構について、ゲノム解析等では理解困難な問題を解き明かすことに有用となり、新たな作用機序に基づく治療・診断法の開発に向けた科学的根拠を提示する。

Research Products

• [Journal Article] A serum microRNA classifier for the diagnosis of sarcomas of various histological subtypes. (2019)
  • Author(s): Asano N, Matsuzaki J, Ichikawa M, Kawauchi J, Takizawa S, Aoki Y, Sakamoto H, Yoshida A, Kobayashi E, Tanzawa Y, Nakayama R, Morioka H, Matsumoto M, Nakamura M, Kondo T, Kato K, Tsuchiya N, Kawai A, Ochiya T
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1299-1299
  • DOI: 10.1038/s41467-019-09143-8
  • Peer Reviewed / Open Access
• [Journal Article] A Nucleolar Stress?Specific p53?miR-101 Molecular Circuit Functions as an Intrinsic Tumor-Suppressor Network (2018)
  • Author(s): Fujiwara Yuko、Saito Motonobu、Robles Ana I.、Nishida Momoyo、Takeshita Fumitaka、Watanabe Masatoshi、Ochiya Takahiro、Yokota Jun、Kohno Takashi、Harris Curtis C.、Tsuchiya Naoto
  • Journal Title: EBioMedicine Volume: 33 Pages: 33-48
  • DOI: 10.1016/j.ebiom.2018.06.031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] CMTM6 is a potential metastasis regulator of EWS cells. (2018)
  • Author(s): Yuko Nishiyama, Naofumi Asano, Tadashi Kondo, Naoto Tsuchiya.
  • Organizer: AACR annual meeting
  • Int'l Joint Research
• [Presentation] Development of diagnostic method for bone and soft tissue sarcomas of various histological subtypes using serum microRNA profiles. (2018)
  • Author(s): Naofumi Asano, Juntaro Matsuzaki, Junpei Kawauchi, Satoko Takizawa, Eisuke Kobayashi, Robert Nakayama, Masaya Nakamura, Morio Matsumoto, Tadashi Kondo, Ken Kato, Naoto Tsuchiya, Akira Kawai, Takahiro Ochiya
  • Organizer: ASCO annual meeting
  • Int'l Joint Research
• [Presentation] 肉腫におけるCMTM6による転移発症の分子ネットワークの解析 (2018)
  • Author(s): 西山郵子、浅野尚文、近藤格、土屋直人
  • Organizer: 第７７回日本がん学会学術総会