腸内微生物群は変異したp53を腫瘍抑制から腫瘍誘発に切り替える

Eliran Kadosh¹, Irit Snir-Alkalay¹, Avanthika Venkatachalam¹

¹The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Nature

|July 31, 2020

まとめ

機能の獲得p53変異は期待に反して腸内の腫瘍を抑制できます腸内微生物群特にガリック酸は WNT信号を活性化することでこの抑制効果を逆転させます

科学分野:

腫瘍学
分子生物学
微生物群の研究

背景:

癌ではp53の体内変異が頻繁に見られ,しばしば腫瘍の成長を促す.
WNTが誘発する腸がんは一般的であり,p53状態の影響を受けることがあります.

研究の目的:

WNT駆動の腸がんモデルにおけるTrp53 (マウスp53) のホットスポット獲得機能変異の影響を調査する.
異なる腸内セグメントにおける変異性p53の対照的な役割とその腸内微生物との相互作用を理解する.

主な方法:

WNTによる腸がん (Csnk1a1欠損またはApcMin変異) のマウスモデルを使用した.
異なる腸領域と腫瘍オルガノイドにおける Trp53機能増強変異の影響を分析した.
腸内微生物とその代謝産物,特にガリック酸が変異したp53の機能に与える影響を調査した.

主要な成果:

変異したp53は文脈に依存する効果を示した. 遠方の腸では腫瘍を誘発するが,近辺の腸とオーガノイドでは腫瘍を抑制する.
変異したp53による腫瘍抑制には,TCF4染色体結合を防ぐことにより,WNT経路のシグナル伝達を妨害することが含まれていた.
腫瘍抑制効果は腸内微生物群によって取り除かれガリウム酸はこの微生物群による逆転を模倣しました

結論:

機能獲得p53変異は,特定の微小環境で腫瘍抑制剤として作用する,重要な機能的な可塑性を示す.
腸内微生物群は,ガリック酸のような代謝物を介して,変異性p53の腫瘍抑制機能を無効化し,WNT経路の再活性化と腫瘍発生を促進します.
これは,癌の変異結果を調節する微環境の重要な役割を強調しています.

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