Targeting the Hedgehog Pathway in Pediatric Medulloblastoma.
Targeting the Hedgehog Pathway in Pediatric Medulloblastoma.
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DOI：
10.3390/cancers7040880
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发表时间：
2015-10-23
期刊：
影响因子：
5.2
通讯作者：
Yang JY
中科院分区：
文献类型：
--
作者：
Huang SY;Yang JY
髓母细胞瘤（MB），小脑的原始神经外切肿瘤，是最常见的儿童恶性脑肿瘤。MB的原因在很大程度上是未知的，但Hedgehog（Hh）通路的异常激活是导致约30% MB的原因。尽管采用手术切除、放疗和化疗等积极治疗，70%-80%的儿童髓母细胞瘤病例可以得到控制，但大多数接受治疗的患者都会出现毁灭性的副作用。因此，迫切需要开发新的有效治疗策略。Hh信号通过调节三种胶质瘤相关癌基因（Gli 1 -3）转录因子的活性来控制靶基因的转录。本文就目前MB的临床治疗方案及耐药机制进行综述。此外，我们将描述目前已知的分子途径，与刺猬通路的背景下，成神经管细胞瘤和非成神经管细胞瘤癌症的发展。最后，我们将介绍调节Gli 1活性的翻译后修饰，并总结Hh/Gli 1通路的正向和负向调节。为了开发新型的髓母细胞瘤联合治疗，目前的信息相互作用的途径和Hh信号的直接调节应证明是至关重要的。
Medulloblastoma (MB), a primitive neuroectomal tumor of the cerebellum, is the most common malignant pediatric brain tumor. The cause of MB is largely unknown, but aberrant activation of Hedgehog (Hh) pathway is responsible for ~30% of MB. Despite aggressive treatment with surgical resection, radiation and chemotherapy, 70%–80% of pediatric medulloblastoma cases can be controlled, but most treated patients suffer devastating side effects. Therefore, developing a new effective treatment strategy is urgently needed. Hh signaling controls transcription of target genes by regulating activities of the three Glioma-associated oncogene (Gli1-3) transcription factors. In this review, we will focus on current clinical treatment options of MB and discuss mechanisms of drug resistance. In addition, we will describe current known molecular pathways which crosstalk with the Hedgehog pathway both in the context of medulloblastoma and non-medulloblastoma cancer development. Finally, we will introduce post-translational modifications that modulate Gli1 activity and summarize the positive and negative regulations of the Hh/Gli1 pathway. Towards developing novel combination therapies for medulloblastoma treatment, current information on interacting pathways and direct regulation of Hh signaling should prove critical.