潜在的臨床的有用性のある大腸がんのサブセットの脆弱性
Loredana Vecchione1, Valentina Gambino1, Jonne Raaijmakers2
1Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Cell
|April 9, 2016
まとめ
研究者らは,BRAFのような結腸癌の生存に不可欠なRAN結合タンパク質2 (RANBP2) を特定した. RANBP2を抑制すると細胞死が起こり,これらの腫瘍は潜在的に標的治療であるビノレルビンに対する感受性が高まります.
科学分野:
- 腫瘍学
- 分子生物学
- 遺伝学
背景:
- BRAF (V600E) 変異性結腸がん (CCs) は,いくつかの非変異性腫瘍と"BRAFのような"腫瘍と呼ばれる遺伝子発現のサインを共有しています.
- BRAFのような腫瘍は全結腸がんの約20%を占める.
- BRAFのようなCCの特定の脆弱性を特定することは,ターゲットを絞った治療法の開発に不可欠です.
研究 の 目的:
- 遺伝子スクリーンを用いて,BRAFのような結腸癌のサブタイプにおける治療的脆弱性を特定する.
- BRAFのようなCC細胞の生存におけるRANBP2 (NUP358) の役割を調査する.
- BRAFのようなCCに対する標的治療としてのビノレルビンの可能性を調査する.
主な方法:
- BRAF (V600E) CCsで上位調節された shRNAベースの遺伝子スクリーンを利用しました.
- BRAF型と非BRAF型CC細胞生存に対するRANBP2の重要性を評価した.
- RANBP2抑制が細胞ミトーシスと微小管の動態に与える影響を分析した.
- ビノレルビンに対するBRAFのようなCCの感受性をin vitroおよびin vivoで評価した.
主要な成果:
- RANBP2は,BRAFのようなCC細胞の生存に不可欠であるが,BRAFのようなCC細胞ではないと特定された.
- RANBP2の抑制は,特にBRAFのようなCCにおいて,ミトーシス欠陥と細胞死を引き起こした.
- RANBP2の静止は,キネトコアからの微小管の増殖を減少させ,スパインドルの乱れを引き起こした.
- BRAF類似のCCは,非BRAF類似のCCと比較して,ビノレルビンに対する感受性が著しく高かった.
結論:
- RANBP2は,BRAFのような結腸癌の生存要因である.
- このメカニズムは,適切な微小管の動態とミトスの進行を維持するRANBP2の役割に関係しています.
- ビノレルビンは,BRAF型の結腸がん患者の有望な標的治療薬です.
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