Targeting Notch signaling as a novel therapy for retinoblastoma.
Targeting Notch signaling as a novel therapy for retinoblastoma.
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DOI：
10.18632/oncotarget.12142
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发表时间：
2016-10-25
期刊：
影响因子：
--
通讯作者：
Eberhart CG
中科院分区：
文献类型：
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作者：
Asnaghi L;Tripathy A;Yang Q;Kaur H;Hanaford A;Yu W;Eberhart CG
视网膜母细胞瘤是儿童最常见的眼内恶性肿瘤。Notch在视网膜母细胞瘤产生的视网膜细胞中起关键作用，因此我们研究了Notch信号在促进视网膜母细胞瘤增殖中的作用。在化学分析的11个人视网膜母细胞瘤样本中，有10个发现了Hes 1的中度或强烈的核表达，支持Notch在视网膜母细胞瘤生长中的作用。Notch途径组分存在于WERI Rb 1和Y 79视网膜母细胞瘤细胞系中，其中Jag 2和DLL 4比其他配体更高表达，Notch 1和Notch 2比Notch 3更丰富。Notch 1的切割/活性形式在两个系中都可检测到。使用γ-分泌酶抑制剂（GSI）或通过使用短发夹RNA下调Jag 2、DLL 4或CBF 1来实现对该途径的抑制，有效地降低了两个系中的生长、增殖和克隆形成。通过微阵列鉴定Jag 2抑制后CXCR 4和CXCR 7的上调和PI 3 KC 2 β的下调。利用shRNA证实了PI 3 KC 2 β的功能重要性。通过将GSI与美法仑以其IC 50组合发现协同作用。这些发现表明，Notch通路在WERI Rb 1和Y 79以及大多数人视网膜母细胞瘤样品中是活跃的，并表明Notch拮抗剂可能代表一种更有效地治疗视网膜母细胞瘤的新方法。
Retinoblastoma is the most common intraocular malignancy of childhood. Notch plays a key role in retinal cells from which retinoblastomas arise, and we therefore studied the role of Notch signaling in promoting retinoblastoma proliferation. Moderate or strong nuclear expression of Hes1 was found in 10 of 11 human retinoblastoma samples analyzed immunohistochemically, supporting a role for Notch in retinoblastoma growth. Notch pathway components were present in WERI Rb1 and Y79 retinoblastoma lines, with Jag2 and DLL4 more highly expressed than other ligands, and Notch1 and Notch2 more abundant than Notch3. The cleaved/active form of Notch1 was detectable in both lines. Inhibition of the pathway, achieved using a γ-secretase inhibitor (GSI) or by downregulating Jag2, DLL4 or CBF1 using short hairpin RNA, potently reduced growth, proliferation and clonogenicity in both lines. Upregulation of CXCR4 and CXCR7 and downregulation of PI3KC2β were identified by microarray upon Jag2 suppression. The functional importance of PI3KC2β was confirmed using shRNA. Synergy was found by combining GSI with Melphalan at their IC50. These findings indicate that Notch pathway is active in WERI Rb1 and Y79, and in most human retinoblastoma samples, and suggest that Notch antagonists may represent a new approach to more effectively treat retinoblastoma.