Inhibition of fatty acid synthase suppresses neovascularization via regulating the expression of VEGF-A in glioma.
OBJECTIVE
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-VEGF165b.


CONCLUSIONS
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.
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.
Yiqiang
Y
Zhou
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.
Guishan
G
Jin
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.
Ruifang
R
Mi
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.
Junwen
J
Zhang
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.
Jin
J
Zhang
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.
Hengzhou
H
Xu
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.
Sen
S
Cheng
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.
Yunsheng
Y
Zhang
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.
Wenjie
W
Song
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. liufushengs@hotmail.com.
Fusheng
F
Liu
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000098:blood supply* / Q000235:genetics / Q000628:therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I
Fatty acid synthase; Glioma stem cells; Neovascularization; Vascular endothelial growth factor A