腫瘍性BRAFは,分泌されるタンパク質IGFBP7によって媒介される経路を通じて老化とアポトーシスを誘発する

Narendra Wajapeyee¹, Ryan W Serra, Xiaochun Zhu

¹Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Cell

|February 13, 2008

まとめ

BRAFV600E腫瘍遺伝子の活性化により,IGFBP7の分泌が誘発され,逆説的に細胞の成長が止まります. この発見は,メラノーマの発達と潜在的な治療目標に関する新しい洞察を提供します.

科学分野:

腫瘍学腫瘍学
細胞生物学細胞生物学
分子生物学は分子生物学である.

背景:

逆説的に,腫瘍遺伝子の活性化は,老化またはアポトーシスによる細胞増殖を抑制することができます.
この効果を媒介する正確な分子経路は完全に理解されていません.

研究の目的:

BRAFV600Eが誘発する,ヒトの原始細胞における増殖阻害に関与する遺伝子を特定する.
腫瘍遺伝子の媒介による老化とアポトーシスにおける分泌されるタンパク質の役割を明らかにする.

主な方法:

人間のプライマリ・ファイブロブラストとメラノサイトにおける全ゲノムRNA干渉スクリーニング.
BRAF-MEK-ERK信号経路の分析について.
BNIP3Lアップレギュレーションを用いたアポトーシスの評価.
メラノーマ細胞系における再結合IGFBP7 (rIGFBP7) のインビトロ試験.
異種移植されたマウスの体内腫瘍抑制の研究.
人間の皮膚,ネビ,メラノーマのサンプルを免疫ヒスト化学分析.

主要な成果:

17の遺伝子がBRAFV600E媒介の増殖阻害に不可欠であると特定されました.
インスリン類似成長因子結合タンパク質7 (IGFBP7) は,BRAFV600E誘発の衰老とアポトーシスにおいて重要な役割を果たしています.
BRAFV600Eの発現は,IGFBP7の合成と分泌につながり,BRAF-MEK-ERKの信号伝達を阻害する.
IGFBP7は,プロアポプトティックタンパク質BNIP3Lを上調する.
rIGFBP7は,BRAFV600E陽性メラノーマ細胞のアポトーシスを誘発し,腫瘍の成長を vivo で抑制します.
IGFBP7の発現の喪失は,メラノーマ発症における重要な出来事として関与しています.

結論:

IGFBP7は,BRAFV600E誘発の衰老とアポトーシスの主要な媒介者である.
IGFBP7はオトクリン/パラクリンメカニズムで働き,腫瘍性信号伝達を抑制し,細胞死を促進します.
IGFBP7は,BRAFV600E陽性メラノーマの潜在的治療標的である.
IGFBP7の喪失は,メラノーマ発症の重要な要因である.

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