脂肪酸合酶的抑制通过调节胶质瘤中VEGF-A的表达来抑制新血管生成。
Inhibition of fatty acid synthase suppresses neovascularization via regulating the expression of VEGF-A in glioma.
作者信息
Zhou Yiqiang, Jin Guishan, Mi Ruifang, Zhang Junwen, Zhang Jin, Xu Hengzhou, Cheng Sen, Zhang Yunsheng, Song Wenjie, Liu Fusheng
机构信息
Brain Tumor Research Center, Beijing Neurosurgical Institute, Department of Neurosurgery, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing Laboratory of Biomedical Materials, Tiantan Xili 6, Dongcheng District, Beijing, 100050, People's Republic of China.
出版信息
J Cancer Res Clin Oncol. 2016 Dec;142(12):2447-2459. doi: 10.1007/s00432-016-2249-6. Epub 2016 Sep 6.
PURPOSE
Fatty acids (FAs) are essential for membrane lipids biosynthesis and energy consumption in cancer cells. De novo FAs synthesis is catalyzed by fatty acid synthase (FASN), which is overexpressed and correlates with histological grade in glioma. Herein, we focused on the role of FASN in glioma neovascularization.
METHODS
The expression levels of FASN, Ki67 and CD34 were determined using immunohistochemistry (IHC). FASN specific-targeted shRNA and C75 were applied to evaluate the influence of FASN on glioma stem cell proliferation, migration and tube formation ability in vitro. An intracranial glioma model was established to study the effects of FASN on tumor growth and neovascularization in vivo.
RESULTS
IHC staining showed that the expression level of FASN correlated with tumor grade, Ki67 levels and microvessels density (MVD) in human gliomas. Inhibition of FASN using shRNAs or C75 decreased tumor growth, prolonged the overall survival of xenograft mice and decreased MVD in brain tumor sections. Moreover, inhibition of FASN blocked hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor A (VEGF-A) signaling and upregulated the anti-angiogenic isoform-VEGFb.
CONCLUSION
Our results suggest that FASN plays a pivotal role in glioma neovascularization, and inhibition of FASN may be a potential target for anti-angiogenic therapy for glioma.
目的
脂肪酸（FAs）对于癌细胞的膜脂生物合成和能量消耗至关重要。脂肪酸合酶（FASN）催化脂肪酸的从头合成，该酶在胶质瘤中过表达且与组织学分级相关。在此，我们聚焦于FASN在胶质瘤血管生成中的作用。
方法
采用免疫组织化学（IHC）检测FASN、Ki67和CD34的表达水平。应用FASN特异性靶向短发夹RNA（shRNA）和C75评估FASN对胶质瘤干细胞体外增殖、迁移和管形成能力的影响。建立颅内胶质瘤模型以研究FASN对体内肿瘤生长和血管生成的影响。
结果
免疫组化染色显示，FASN的表达水平与人胶质瘤的肿瘤分级、Ki67水平和微血管密度（MVD）相关。使用shRNA或C75抑制FASN可减缓肿瘤生长，延长异种移植小鼠的总生存期，并降低脑肿瘤切片中的MVD。此外，抑制FASN可阻断缺氧诱导因子-1α（HIF-1α）/血管内皮生长因子A（VEGF-A）信号通路，并上调抗血管生成异构体-VEGFb。
结论
我们的结果表明，FASN在胶质瘤血管生成中起关键作用，抑制FASN可能是胶质瘤抗血管生成治疗的潜在靶点。
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