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Study of unconventional protein secretion in cancer

Research Project

Project/Area Number 20K07621
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionJikei University School of Medicine

Principal Investigator

YAMADA Kohji  東京慈恵会医科大学, 医学部, 講師 (90570979)

Co-Investigator(Kenkyū-buntansha) 吉田 彩舟  東京慈恵会医科大学, 医学部, 講師 (40772744)
立花 利公  東京慈恵会医科大学, 医学部, 教授 (80163476)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsタンパク質の多機能性 / 型破り分泌 / タンパク質分泌 / CUPS / 肝がん / PKCδ / 分泌 / マーカー / PKC
Outline of Research at the Start

肝がんは予後が極めて悪い疾患である。現在有効な診断・治療法の創生が求められているが、この社会ニーズを実現するためには、肝腫瘍形成の機構理解が不可欠である。申請者はこれまで分泌シグナルを持たないプロテインキナーゼCデルタ(PKCδ)が生きた肝がん細胞から型破り分泌されることを初めて見出した。また型破り分泌されたPKCδが肝がん細胞の増殖亢進に寄与することも突き止めている。そこで型破り分泌が肝腫瘍形成の機構に関与すると考え、本研究では、PKCδの型破り分泌についてその分子機構を解明するとともに肝腫瘍形成における意義を明らかにする。本研究により型破り分泌を標的とする新しいがん研究領域が創出できる。

Outline of Final Research Achievements

We have previously found that importin α1 and protein kinase C delta (PKCδ) are released from proliferating cancer cells. In this period, we have made two major discoveries. First, we found that PKCδ is highly detected in the serum of patients with hepatocellular carcinoma, while it is low in the serum of healthy subjects and patients with chronic hepatitis. In particular, it is detected in patients with very early-stage cancer, suggesting that it may be a novel biomarker. Second is the elucidation of the secretion mechanism. Using PKCδ as a model, we used the proximity labeling method to analyze the secretory pathway of PKCδ and found a vesicular trafficking pathway originating from the endoplasmic reticulum. The characteristics of the unconventional secretion of this cytoplasmic protein found in liver cancer include: 1) it occurs under normal culture conditions, 2) it originates from the endoplasmic reticulum, and 3) it contributes to tumorigenesis.

Academic Significance and Societal Importance of the Research Achievements

通常、腫瘍組織の外液成分における細胞質タンパク質のほとんどは細胞膜破壊による漏出と考えられてきた。一方で本研究により、細胞質タンパク質の一部は分泌され、肝がん特異性が高く、腫瘍形成に積極的に寄与することを突き止めた。特に、プロテインキナーゼCデルタ(PKCδ)に関しては早期診断用の血液バイオマーカーになる可能性があるのみならず、細胞外PKCδまたはその分泌機構が治療標的になる可能性が高く、肝がん医療における臨床的意義は大きい。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (10 results)

All 2023 2022 2021 2020

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (1 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] Cancer-Related Unconventional Protein Secretion: A New Role of the Endoplasmic Reticulum2023

    • Author(s)
      Yamada Kohji、Yoshida Kiyotsugu
    • Journal Title

      DNA and Cell Biology

      Volume: 42 Issue: 5 Pages: 1-4

    • DOI

      10.1089/dna.2023.0044

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of protein kinase C delta leads to cellular senescence to induce anti‐tumor effects in colorectal cancer2023

    • Author(s)
      Shimoyama Yuya、Yamada Kohji、Yoshida Saishu、Kawamura Akira、Hannya Yoshito、Imaizumi Yuta、Kumamoto Tomotaka、Takeda Yasuhiro、Shimoda Masayuki、Eto Ken、Yoshida Kiyotsugu
    • Journal Title

      Cancer Science

      Volume: in press Issue: 6 Pages: 2471-2484

    • DOI

      10.1111/cas.15768

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Leakage? or Secretion? unconventional protein secretion in cancer2023

    • Author(s)
      Yamada Kohji、Yoshida Kiyotsugu
    • Journal Title

      Oncotarget

      Volume: 14 Issue: 1 Pages: 146-147

    • DOI

      10.18632/oncotarget.28368

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Protein Kinase C Delta Is a Novel Biomarker for Hepatocellular Carcinoma.2023

    • Author(s)
      Oikawa T, Yamada K, Tsubota A, Saeki C, Tago N, Nakagawa C, Ueda K, Kamioka H, Taniai T, Haruki K, Nakano M, Torisu Y, Ikegami T, Yoshida K, and Saruta M.
    • Journal Title

      Gastro Hep Advances

      Volume: 2 Issue: 1 Pages: 83-95

    • DOI

      10.1016/j.gastha.2022.07.020

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extended-synaptotagmin 1 engages in unconventional protein secretion mediated via SEC22B<sup>+</sup>vesicle pathway in liver cancer2022

    • Author(s)
      Yamada Kohji、Motohashi Saya、Oikawa Tsunekazu、Tago Naoko、Koizumi Rei、Ono Masaya、Tachibana Toshiaki、Yoshida Ayano、Yoshida Saishu、Shimoda Masayuki、Oka Masahiro、Yoneda Yoshihiro、Yoshida Kiyotsugu
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 119 Issue: 36

    • DOI

      10.1073/pnas.2202730119

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multiple subcellular localizations and functions of protein kinase Cδ in liver cancer2022

    • Author(s)
      Yamada Kohji、Yoshida Kiyotsugu
    • Journal Title

      World Journal of Gastroenterology

      Volume: 28 Issue: 2 Pages: 188-198

    • DOI

      10.3748/wjg.v28.i2.188

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Unconventional Secretion of PKCδ Exerts Tumorigenic Function via Stimulation of ERK1/2 Signaling in Liver Cancer2020

    • Author(s)
      Yamada Kohji、Oikawa Tsunekazu、Kizawa Ryusuke、Motohashi Saya、Yoshida Saishu、Kumamoto Tomotaka、Saeki Chisato、Nakagawa Chika、Shimoyama Yuya、Aoki Katsuhiko、Tachibana Toshiaki、Saruta Masayuki、Ono Masaya、Yoshida Kiyotsugu
    • Journal Title

      Cancer Research

      Volume: 81 Issue: 2 Pages: 414-425

    • DOI

      10.1158/0008-5472.can-20-2009

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Extracellular localization of PKCδand its function as a growth factor to activate ERK signaling in liver cancer2021

    • Author(s)
      山田幸司、及川恒一、本橋沙耶、吉田彩乃、小泉麗、吉田清嗣
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Research-status Report
  • [Patent(Industrial Property Rights)] PKCδとE-Syt1との相互作用阻害剤を含む新規肝癌治療薬2022

    • Inventor(s)
      山田幸司、本橋沙耶、吉田清嗣
    • Industrial Property Rights Holder
      山田幸司、本橋沙耶、吉田清嗣
    • Industrial Property Rights Type
      特許
    • Filing Date
      2022
    • Related Report
      2021 Research-status Report
  • [Patent(Industrial Property Rights)] 細胞外のPKCδを標的とする肝癌細胞増殖抑制剤及びそれを含む新規肝癌治療薬2020

    • Inventor(s)
      山田幸司、木澤隆介、吉田清嗣
    • Industrial Property Rights Holder
      慈恵大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-168678
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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