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Molecular biological analysis of disorders of energy metabolism and mechanisms of Immune Escape in cancer in renal cell carcinoma

Research Project

Project/Area Number 20K09546
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56030:Urology-related
Research InstitutionDokkyo Medical University

Principal Investigator

kamai takao  獨協医科大学, 医学部, 教授 (80316562)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords腎細胞癌 / FH / SDH / HLRCC / Keap1 / Nrf2 / NGS
Outline of Research at the Start

我々は、TCA回路の構成因子あるFH、癌遺伝子であるAkt、転写因子であるNrf2の3つの経路の異常が関連性を持って腎細胞癌の進展に関与していること、一方で、インターフェロン(IFN)経路とAkt経路の異常亢進状態では、腫瘍誘導性にPD-L1の発現が高くなることを報告した。
今回我々は、細胞の生命活動のエネルギー源であるTCA回路のメンバー(FH、SDH等)や、抗酸化作用とエネルギー代謝に関係しているKeap1、Nrf2の遺伝子やタンパク質レベルでの異常が、免疫回避にどのような影響を与えているのかについて解析し、腎細胞癌におけるエネルギー代謝異常と免疫回避機構との関連性を検討する。

Outline of Final Research Achievements

We reported (1)Elevated expression of PD-L1 by tumor cells and a higher TILD were associated with a worse histological grade, higher pT stage, and higher peripheral blood neutrophil-to-lymphocyte ratio. Elevated expression of PD-L1 by tumor cells, a higher TILD, and type I, III, or IV tumors with elevated expression of either PD-L1 or TILD showed a positive correlation with poorer diferentiation and local invasion. (2)This study assessed the role of SDHA gene mutations in human RCC. Targeted next-generation sequencing and direct Sanger sequencing revealed single nucleotide variants (SNVs) of the SDHA gene with amino acid sequence variations in 11/129 tumors, while no SDHB/C/D gene mutations were found. Tumor cells with SNVs of the SDHA gene were characterized by eosinophilic cytoplasm and various patterns of proliferation.

Academic Significance and Societal Importance of the Research Achievements

(1)腫瘍微小環境におけるPD-L1の発現とthe tumor-infltrating lymphocyte density (TILD)がupper urinary tract urothelial carcinoma (UTUC)の進行に影響を与えることを示した。したがって、この癌のより効果的な治療戦略を開発するには、腫瘍微小環境の免疫学的特性を解明する重要性を明らかにした。(2)この研究では、SDH欠損腎細胞癌(RCC)においてはSDHA遺伝子の一塩基変異体(SNVs)が129例中11例に検出され、SDHB/C/D遺伝子変異は検出されないことを明らかにした。

Report

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

    (4 results)

All 2022

All Journal Article (3 results) (of which Peer Reviewed: 3 results) Presentation (1 results)

  • [Journal Article] Increased expression of Nrf2 and elevated glucose uptake in pheochromocytoma and paraganglioma with SDHB gene mutation2022

    • Author(s)
      Kamai Takao、Murakami Satoshi、Arai Kyoko、Nishihara Daisaku、Uematsu Toshitaka、Ishida Kazuyuki、Kijima Toshiki
    • Journal Title

      BMC Cancer

      Volume: 22 Issue: 1 Pages: 289-289

    • DOI

      10.1186/s12885-022-09415-5

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Circulating tumor cells and cell-free tumor DNA analyses in urothelial cancer using the LiquidBiopsy platform2022

    • Author(s)
      Kobayashi Minoru、Abe Hideyuki、Arai Kyoko、Murakami Satoshi、Kamai Takao
    • Journal Title

      Current Urology

      Volume: 16 Issue: 2 Pages: 99-106

    • DOI

      10.1097/cu9.0000000000000091

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association of Nrf2 expression and mutation with Weiss and Helsinki scores in adrenocortical carcinoma2022

    • Author(s)
      Kamai Takao、Murakami Satoshi、Arai Kyoko、Ishida Kazuyuki、Kijima Toshiki
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 7 Pages: 2368-2377

    • DOI

      10.1111/cas.15379

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Presentation] 部尿路上皮癌におけるPD-L1およびFAPの発現と臨床的/病理学的因子との関連2022

    • Author(s)
      西原大策、木島敏樹、貫井昭徳、新井京子、釜井隆男:
    • Organizer
      第99回日本泌尿器科学会栃木地方会
    • Related Report
      2022 Annual Research Report

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

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