Lipid metabolism enzyme ACSVL3 supports glioblastoma stem cell maintenance and tumorigenicity.
Lipid metabolism enzyme ACSVL3 supports glioblastoma stem cell maintenance and tumorigenicity.
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DOI：
10.1186/1471-2407-14-401
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发表时间：
2014-06-04
期刊：
影响因子：
3.8
通讯作者：
Laterra J
中科院分区：
文献类型：
--
作者：
Sun P;Xia S;Lal B;Shi X;Yang KS;Watkins PA;Laterra J
以细胞代谢为靶点为治疗癌症的药物的开发提供了有希望的机会。我们先前发现脂肪酰辅酶A合成酶VL3(ACSVL3)在恶性脑肿瘤组织中升高，并参与肿瘤的发生。本研究探讨ACSVL3在维持多形性胶质母细胞瘤(GBM)干细胞自我更新中的作用，以及GBM干细胞启动肿瘤异种移植形成的能力。我们检测了几种富含GBM干细胞的神经球培养物在分化过程中ACSVL3的表达。为了研究ACSVL3的功能，我们使用小干扰RNA靶向ACSVL3来进行功能丧失，并检测了干细胞标记物的表达、神经球的形成和肿瘤的启动特性。在富含GBM干细胞的神经球培养中，ACSVL3的表达水平显著增加，分化后表达水平降低。下调ACSVL3和小的抑制RNA减少了与干细胞自我更新相关的标志物和调节因子的表达，包括CD133、ALDH、Musashi-1和SOX-2。在神经球细胞中，ACSVL3基因敲除导致分化标志物GFAP和Tuj1表达增加。此外，ACSVL3基因敲除降低了这些富含GBM干细胞的神经球培养物的非贴壁神经球细胞生长、神经球形成能力和自我更新能力。体内研究表明，ACSVL3功能丧失实质上抑制了神经球细胞在原位肿瘤移植瘤中的增殖能力。ACSVL3的表达受支持GBM干细胞自我更新和肿瘤起始的受体酪氨酸激酶通路的调节，包括EGFR和HGF/c-Met通路，进一步证实了ACSVL3与肿瘤干细胞表型之间的联系。我们的发现表明，脂代谢酶ACSVL3参与了动物GBM干细胞的维持和GBM干细胞富集神经球的致瘤能力。
Targeting cell metabolism offers promising opportunities for the development of drugs to treat cancer. We previously found that the fatty acyl-CoA synthetase VL3 (ACSVL3) is elevated in malignant brain tumor tissues and involved in tumorigenesis. This study investigates the role of ACSVL3 in the maintenance of glioblastoma multiforme (GBM) stem cell self-renewal and the capacity of GBM stem cells to initiate tumor xenograft formation. We examined ACSVL3 expression during differentiation of several GBM stem cell enriched neurosphere cultures. To study the function of ACSVL3, we performed loss-of-function by using small interfering RNAs to target ACSVL3 and examined stem cell marker expression, neurosphere formation and tumor initiation properties. ACSVL3 expression levels were substantially increased in GBM stem cell enriched neurosphere cultures and decreased after differentiation of the neurospheres. Down-regulating ACSVL3 with small inhibiting RNAs decreased the expression of markers and regulators associated with stem cell self-renewal, including CD133, ALDH, Musashi-1 and Sox-2. ACSVL3 knockdown in neurosphere cells led to increased expression of differentiation markers GFAP and Tuj1. Furthermore, ACSVL3 knockdown reduced anchorage-independent neurosphere cell growth, neurosphere-forming capacity as well as self-renewal of these GBM stem cell enriched neurosphere cultures. In vivo studies revealed that ACSVL3 loss-of-function substantially inhibited the ability of neurosphere cells to propagate orthotopic tumor xenografts. A link between ACSVL3 and cancer stem cell phenotype was further established by the findings that ACSVL3 expression was regulated by receptor tyrosine kinase pathways that support GBM stem cell self-renewal and tumor initiation, including EGFR and HGF/c-Met pathways. Our findings indicate that the lipid metabolism enzyme ACSVL3 is involved in GBM stem cell maintenance and the tumor-initiating capacity of GBM stem cell enriched-neurospheres in animals.
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DOI：
10.1083/jcb.200207080
发表时间：
2003-06-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Herrmann T;van der Hoeven F;Grone HJ;Stewart AF;Langbein L;Kaiser I;Liebisch G;Gosch I;Buchkremer F;Drobnik W;Schmitz G;Stremmel W
通讯作者：
Stremmel W
影响因子：
8.8
作者：
Mashima, T.;Seimiya, H.;Tsuruo, T.
通讯作者：
Tsuruo, T.
影响因子：
5.2
作者：
Sun, Peng;Xia, Shuli;Lal, Bachchu;Eberhart, Charles G.;Quinones-Hinojosa, Alfredo;Maciaczyk, Jarek;Matsui, William;DiMeco, Francesco;Piccirillo, Sara M.;Vescovi, Angelo L.;Laterra, John
通讯作者：
Laterra, John
影响因子：
5.2
作者：
Bar, Eli E.;Chaudhry, Aneeka;Eberharta, Charles G.
通讯作者：
Eberharta, Charles G.
影响因子：
11.5
作者：
Orita, Hajime;Coulter, Jonathan;Gabrielson, Edward
通讯作者：
Gabrielson, Edward