Merlin/NF2 Regulates Angiogenesis in Schwannomas through a Rac1/Semaphorin 3F-Dependent Mechanism
Merlin/NF2 Regulates Angiogenesis in Schwannomas through a Rac1/Semaphorin 3F-Dependent Mechanism
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DOI：
10.1593/neo.111600
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发表时间：
2012-02-01
期刊：
影响因子：
4.8
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
--
作者：
Wong, Hon-Kit;Shimizu, Akio;Jain, Rakesh K.
2 型神经纤维瘤病 (NF2) 是一种常染色体显性多发性肿瘤综合征，由 NF2 抑癌基因突变引起。 NF2 患者会出现标志性神经鞘瘤，需要手术或放疗，这两种方法都会产生显着的副作用。最近的研究表明，神经鞘瘤的肿瘤微环境，特别是肿瘤血管，可能是一个重要的治疗靶点。此外，尽管人们已经做了很多工作来了解 merlin（NF2 基因产物）如何作为神经鞘瘤细胞中的肿瘤抑制基因发挥作用，但 merlin 在肿瘤微环境中的功能作用以及 merlin 调节血管生成以支持神经鞘瘤生长的机制在很大程度上尚未被探索。在这里，我们报道了信号蛋白 3F (SEMA3F) 的表达在缺乏 merlin/NF2 的神经鞘瘤细胞中特异性下调。当我们在神经鞘瘤细胞中重新引入 SEMA3F 时，我们观察到携带 merlin 缺陷型脑肿瘤的裸鼠的肿瘤血管正常化、肿瘤负荷减少并延长了生存期。接下来，使用化学抑制剂和RNA干扰基因敲除，我们发现merlin通过Rho GTPase家族成员Rac1调节SEMA3F的表达。这项研究表明，merlin除了具有肿瘤抑制活性外，还通过调节SEMA3F等抗血管生成因子来维持神经系统中的生理性血管生成。恢复神经鞘瘤微环境中促血管生成和抗血管生成因子的相对平衡，例如 SEMA3F 的增加，可能是缓解 NF2 相关神经鞘瘤临床症状的新策略。
Neurofibromatosis type 2 (NF2) is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumor suppressor gene. Patients with NF2 develop hallmark schwannomas that require surgery or radiation, both of which have significant adverse effects. Recent studies have indicated that the tumor microenvironment-in particular, tumor blood vessels-of schwannomas may be an important therapeutic target. Furthermore, although much has been done to understand how merlin, the NF2 gene product, functions as a tumor suppressor gene in schwannoma cells, the functional role of merlin in the tumor microenvironment and the mechanism(s) by which merlin regulates angiogenesis to support schwannoma growth is largely unexplored. Here we report that the expression of semaphorin 3F (SEMA3F) was specifically downregulated in schwannoma cells lacking merlin/NF2. When we reintroduced SEMA3F in schwannoma cells, we observed normalized tumor blood vessels, reduced tumor burden, and extended survival in nude mice bearing merlin-deficient brain tumors. Next, using chemical inhibitors and gene knockdown with RNA interference, we found that merlin regulated expression of SEMA3F through Rho GTPase family member Rac1. This study shows that, in addition to the tumor-suppressing activity of merlin, it also functions to maintain physiological angiogenesis in the nervous system by regulating antiangiogenic factors such as SEMA3F. Restoring the relative balance of proangiogenic and antiangiogenic factors, such as increases in SEMA3F, in schwannoma microenvironment may represent a novel strategy to alleviate the clinical symptoms of NF2-related schwannomas.