肥満はSTAT-1依存性NASHとSTAT-3依存性HCCを誘発する

Marcus Grohmann¹, Florian Wiede², Garron T Dodd¹

¹Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.

Cell

|November 21, 2018

まとめ

肥満は酸化ストレスを生み出すことで肝がん (HCC) を含む癌を誘発しますこのストレスは,非アルコール性脂肪肝炎 (NASH),線維症,HCCの発症の明確な経路につながる,TCPTPを無効化する.

科学分野:

ヘパトロジー
腫瘍学
免疫学

背景:

肥満は様々な癌,特に肝細胞癌 (HCC) の重要な危険因子です.
肥満,非アルコール性脂肪肝炎 (NASH),線維症,肝硬変,HCCとの間の確立された関連は,連続的な進行を示唆しています.
肥満に起因するHCCでは,これらの状態の潜在的分離が示唆されている.

研究の目的:

肥満に関連した肝臓病原性におけるT細胞タンパク質チロシンフォスファテーゼ (TCPTP) の役割を調査する.
NASHと線維症が肥満におけるHCCの発症の前提条件であるかどうかを判断する.
NASH,線維症,HCCに対する酸化ストレスによる独立した貢献を解明する.

主な方法:

肥満C57BL/ 6のマウスを利用し,肝細胞特異のTCPTPを削除した.
NASH/線維症とは無関係にHCCの発症を評価するために,化学的発がん剤を投与した.
STAT-1とSTAT-3の信号経路を操作した

主要な成果:

肝細胞におけるTCPTPの消去は,肥満マウスのT細胞増殖,NASH,線維症,HCCを促した.
STAT-1シグナリングの抑制はT細胞の募集を減少させ,NASH/繊維症を誘発するが,HCCは誘発しない.
STAT-3シグナリングの修正は,NASH/線維症に影響を与えることなく,HCCを予防しました.
NASH / 線維症なしに,TCPTPの消去は,発がん剤に誘発されたHCCを加速しました.

結論:

肥満に起因する肝臓の酸化ストレスは NASH,線維症,HCCを独立して引き起こします.
このモデルでは,STAT-3のシグナル伝達がHCCの発達に不可欠であり,STAT-1はNASHと線維症により関与しています.
NASHと線維症は,肥満におけるHCCの発症の必須段階ではない.

キーワード:

PTPN2 について STAT-1 について STAT-3 について T細胞繊維症肝細胞がん非アルコール性脂肪肝炎非アルコール性脂肪肝肥満酸化ストレスタンパク質チロシン・フォスファターゼ

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