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Development of Innovative Hepatocellular Carcinoma Therapies Targeting Cancer Metabolism and Tumor Immunity Regulated by MYC and PGC1a

Research Project

Project/Area Number 22K15545
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionKumamoto University

Principal Investigator

Kitano Yuki  熊本大学, 病院, 特任助教 (40814760)

Project Period (FY) 2022-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2023: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords肝細胞癌 / がん代謝 / 腫瘍免疫 / 癌代謝 / MYC / PGC1α
Outline of Research at the Start

“がん代謝”は、がん細胞の発育・進展において非常に重要な役割を担っている。正常細胞はミトコンドリア内での酸化的リン酸化を中心に、がん細胞は解糖系を亢進することでATPを産生している。本研究では解糖系のmaster regulatorとしてMYCを、酸化的リン酸化の regulatorとしてPGC1αを同定した。“腫瘍免疫” に着目した治療標的探索の重要性は近年急速に高まっており、これらの免疫回避機構に関わるメカニズム解明は極めて重要な研究課題である。本研究では肝細胞癌においてMYCとPGC1α らに制御される“がん代謝”が“腫瘍免疫”に与える影響と、癌の進展に関与するメカニズム解明を目的とした。

Outline of Final Research Achievements

This study aims to elucidate the impact of "cancer metabolism" regulated by MYC and PGC1a on "tumor immunity" and mechanisms involved in cancer progression in hepatocellular carcinoma (HCC).
Analysis of TCGA datasets revealed that in HCC, the high expression of MYC (HR=1.75, P=0.008) and the low expression group of PGC1a (HR=2.33, P<0.0001) had a worse prognosis. A signature combining the expression levels of cancer metabolism-related genes including MYC and PGC1a revealed enhanced glycolysis in poorly differentiated HCC. In 225 resected specimens of HCC, the expression of immune cells was examined within the tumor and at its periphery. At the tumor periphery, the low expression of CD8+ T cells and the high expression of tumor-infiltrating neutrophils and macrophages were significantly associated with poorer prognosis. Assessment of the tumor immune environment using immune cells revealed that cold tumors were significantly associated with worse prognosis compared to hot tumors.

Academic Significance and Societal Importance of the Research Achievements

本研究では、肝細胞癌においてMYC, PGC1αらに制御される“がん代謝”が“腫瘍免疫”に与える影響と、癌の進展に関与するメカニズム解明を目的とした。
がん代謝制御因子であるMYCとPGC1αの発現レベルが肝細胞癌患者の生命予後に関与し、さらに悪性度の高い低分化肝細胞癌でがん代謝が亢進していることが分かった。さらに肝細胞癌腫瘍周辺の腫瘍免疫環境(hot/cold tumor)も予後に関与することが分かった。これらの結果より、肝細胞癌においてがん代謝と腫瘍免疫は非常に重要な役割を果たしており、MYCとPGC1αは治療標的となり得ることを示した。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (2 results)

All 2022

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results)

  • [Journal Article] Survival impact of immune cells infiltrating peritumoral area of hepatocellular carcinoma2022

    • Author(s)
      Yusa Toshihiko、Yamashita Yo‐ichi、Okabe Hirohisa、Nakao Yosuke、Itoyama Rumi、Kitano Yuki、Kaida Takayoshi、Miyata Tatsunori、Mima Kosuke、Imai Katsunori、Hayashi Hiromitsu、Baba Hideo
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 12 Pages: 4048-4058

    • DOI

      10.1111/cas.15437

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cancer-associated fibroblast senescence and its relation with tumour-infiltrating lymphocytes and PD-L1 expressions in intrahepatic cholangiocarcinoma2022

    • Author(s)
      2.Lan C, Kitano Y, Yamashita YI, Yamao T, Kajiyama K, Yoshizumi T, Fukuzawa K, Sugimachi K, Ikeda Y, Takamori H, Miyanari N, Hirota M, Baba H
    • Journal Title

      British Journal of Cancer

      Volume: 126 Issue: 2 Pages: 219-227

    • DOI

      10.1038/s41416-021-01569-6

    • Related Report
      2022 Research-status Report
    • Peer Reviewed

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Published: 2022-04-19   Modified: 2025-01-30  

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