Study of metabolic reprogramming and immune evasion in renal cell carcinoma

• Project/Area Number: 17K11156
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Dokkyo Medical University
• Principal Investigator: Kamai Takao 獨協医科大学, 医学部, 教授 (80316562)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 腎細胞癌 / 代謝異常 / 免疫回避 / Nrf2 / Warburg effect / renal cell carcinoma / Akt / PD-L1 / 免疫 / インターフェロン / 腎癌

Outline of Final Research Achievements

We investigated SNPs for IFN-lambda3 in 53 patients with metastatic renal cell carcinoma (RCC). In 16 patients who were heterozygous or homozygous for the minor alleles of SNPs for IFN-lambda3, the primary tumors showed elevated glucose uptake, and increased expression of phosphorylated Akt and PD-L1. These patients had a worse response to treatment with sequential vascular endothelial growth factor-targeting therapy, and showed shorter survival compared with patients who had the major alleles.
The study included 89 patients who underwent renal surgery for RCC. In 89 patients whose tumors showed higher Nrf2 expression, there was a more rapid decrease of estimated glomerular filtration rate (eGFR) and increase of serum uric acid (SUA) after nephrectomy. Multivariate analysis confirmed that increased Nrf2 expression was an independent poor prognostic factor related to shorter overall survival.

Academic Significance and Societal Importance of the Research Achievements

癌ではエネルギー代謝異常（酸素からブドウ糖へのエネルギー源のシフト）や免疫回避（免疫細胞からの攻撃をかわす）が見られますが、実際に摘出した手術組織を用いて、腎細胞癌におけるエネルギー代謝異常を、中学生で学ぶTCA回路（クエン酸回路）におけるFHやSDHの遺伝子やタンパク質の異常で解析し、また、免疫回避機構の異常をPD-L1のタンパク質の異常を検討できたことは学術的な意義があると考えます。更に、抗酸化作用も癌の抑制に関与していることが知られていますが、この抗酸化作用に中心的な役割を果たしているNrf2の遺伝子変異やタンパク発現異常が腎細胞癌の進行と関連があることも報告できました。

Research Products

• [Journal Article] Nrf2 gene mutation and single nucleotide polymorphism rs6721961 of the Nrf2 promoter region in renal cell cancer (2019)
  • Author(s): Yamaguchi Yoshiyuki、Kamai Takao、Higashi Satoru、Murakami Satoshi、Arai Kyoko、Shirataki Hiromichi、Yoshida Ken-Ichiro
  • Journal Title: BMC Cancer Volume: 19 Issue: 1 Pages: 1137-1137
  • DOI: 10.1186/s12885-019-6347-0
  • Peer Reviewed / Open Access
• [Journal Article] Germline polymorphism of interferon-lambda3 is clinically associated with progression of renal cell carcinoma (2018)
  • Author(s): Nukui A, Yanai Y, Tsuzuki T, Abe H, Arai K, Yoshida K, Kamai T
  • Journal Title: Oncotarget Volume: 9 Issue: 3 Pages: 4188-4199
  • DOI: 10.18632/oncotarget.23683
  • Peer Reviewed / Open Access
• [Journal Article] Increased Nrf2 expression by renal cell carcinoma is associated with postoperative chronic kidney disease and an unfavorable prognosis. (2018)
  • Author(s): Yuki H, Kamai T, Murakami S, Higashi S, Narimatsu T, Kambara T, Betsunoh H, Abe H, Arai K, Shirataki H, Yoshida KI.
  • Journal Title: Oncotarget Volume: 9 Issue: 47 Pages: 28351-28363
  • DOI: 10.18632/oncotarget.25322
  • Peer Reviewed / Open Access
• [Journal Article] Clinically significant association of elevated expression of nuclear factor E2-related factor 2 expression with higher glucose uptake and progression of upper urinary tract cancer. (2018)
  • Author(s): Nukui A, Narimatsu T, Kambara T, Abe H, Sakamoto S, Yoshida KI, Kamai T.
  • Journal Title: BMC Cancer Volume: 2018 Issue: 1 Pages: 493-493
  • DOI: 10.1186/s12885-018-4427-1
  • Peer Reviewed / Open Access