Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis.
Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis.
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DOI：
10.1038/onc.2009.360
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发表时间：
2010-01-21
期刊：
影响因子：
8
通讯作者：
Ratner, N.
中科院分区：
文献类型：
--
作者：
Miller, S. J.;Lan, Z. D.;Hardiman, A.;Wu, J.;Kordich, J. J.;Patmore, D. M.;Hegde, R. S.;Cripe, T. P.;Cancelas, J. A.;Collins, M. H.;Ratner, N.
恶性周围神经鞘瘤（MPNST）是一种侵袭性肉瘤，目前尚无有效的治疗方法。生物信息学被用来确定潜在的治疗靶点。配对盒（PAX），眼睛缺席（EYA），DACH（DACH）和Sine Oculis（SIX）基因，在果蝇中形成了一个相互调节的网络，被发现在人类MPNST细胞系和实体瘤中失调。我们发现DACH 1表达减少，PAX 6、EYA 1、EYA 2、EYA 4和SIX 1 - 4表达增加。与观察结果一致的是，在1型神经纤维瘤病患者中有一半的MPNST发生在NF 1突变之后，我们发现NF 1-GAP相关结构域（GRD）的外源性表达使DACH 1表达正常化。在大多数MPSNT细胞系中，通过定量真实的时间PCR估计，EYA 4 mRNA升高超过100倍。在体外，使用shRNA抑制EYA 4表达减少了细胞粘附和迁移，并导致细胞坏死，而不影响细胞增殖或凋亡性细胞死亡。表达sh-EYA 4的MPNST细胞在裸鼠中不能形成肿瘤或形成非常小的肿瘤，具有广泛的坏死，但与对照细胞相似的增殖和凋亡水平。我们的研究结果确定了EYA 4和可能相互作用的SIX和DACH蛋白在MPNST中的作用，并建议EYA 4途径作为合理的治疗靶点。
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas without effective therapeutics. Bioinformatics was used to identify potential therapeutic targets. Paired Box (PAX), Eyes Absent (EYA), Dachsund (DACH), and Sine Oculis (SIX) genes, which form a regulatory interactive network in drosophila, were found to be dysregulated in human MPNST cell lines and solid tumors. We identified a decrease in DACH1 expression, and increases in expression of PAX6, EYA1, EYA2, EYA4, and SIX1- 4. Consistent with the observation that half of MPNSTs develop in neurofibromatosis type 1 patients, subsequent to NF1 mutation, we found that exogenous expression of the NF1-GAP related domain (GRD) normalized DACH1 expression. EYA4 mRNA was elevated more than 100-fold as estimated by quantitative real time PCR in most MPSNT cell lines. In vitro, suppression of EYA4 expression using shRNA reduced cell adhesion and migration and caused cellular necrosis without affecting cell proliferation or apoptotic cell death. MPNST cells expressing sh-EYA4 either failed to form tumors in nude mice or formed very small tumors, with extensive necrosis but similar levels of proliferation and apoptosis as control cells. Our findings identify a role for EYA4 and possibly interacting SIX and DACH proteins in MPNSTs and suggest the EYA4 pathway as a rational therapeutic target.
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