Analysis of the intestinal flora of ACLY and its effect for carcinogenesis

2023 Fiscal Year Final Research Report

• Project/Area Number: 18K07251
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Research Institute for Clinical Oncology Saitama Cancer Center
• Principal Investigator: Kanda Hiroaki 地方独立行政法人埼玉県立病院機構埼玉県立がんセンター(臨床腫瘍研究所), 病院 病理診断科, 科長(兼)診療部長 (90260067)
• Project Period (FY): 2018-04-01 – 2024-03-31
• Keywords: ATP-citrate lyase / マウス / リンパ腫 / メタゲノム

Outline of Final Research Achievements

ATP-citrate lyase (ACLY) catalyzes the generation of acetyl-CoA from citrate. ACLY expression is upregulated and/or ACLY is phosphorylated in several types of cancer. We generated ACLY transgenic mice (Tg) to examine the role of ACLY in carcinogenesis. Tg with C57BL/B6 background spontaneously developed lymphoma/leukemia (LL), frequently. But control mice developed LL, too. Then, the Tg were back-crossed with C3H mice, which are resistant to LL. About 20% of Tg developed LL, spontaneously. No LL was seen in the controls. This study suggests that ACLY might contribute to LL development. Since the bleeding method was different between C57BL/B6 and C3H experiments, one possible cause of LL development, especially in control mice, might be owing to the intestinal flora. Metagenomic analysis revealed that there was difference of intestinal flora between Tg and control mice using bleeding.

Free Research Field

病理学

Academic Significance and Societal Importance of the Research Achievements

ACLY（ATPクエン酸解裂酵素）は脂肪酸やコレステロールを合成する主要な経路を担っている。この酵素は多種のがんで発現亢進がみられるため、われわれはがん細胞におけるこの酵素の役割を検討してきた。その一環としてヒトACLYを導入したトランスジェニックマウスを作成して観察したところ、リンパ腫が多発し、この蛋白とリンパ腫の関連が疑われた。この発がんメカニズムに関し、マウス飼育法の検討から、腸内細菌叢の関与が疑われた。調べてみるとトランスジェニックマウスではコントロールマウスとは異なった腸内細菌叢を有することがわかった。現在、原因細菌の同定を試みるなどの実験を行っている。