AEG-1: Novel Gene Involved in Malignant Glioma

描述(申请人提供)：恶性胶质瘤是所有脑癌中最致命的。肿瘤侵入周围组织，因此限制了手术切除的完全切除，导致复发。识别与胶质瘤侵袭有关的分子是开发合理的靶向有效治疗方法的重要一步。我们已经证明星形胶质细胞升高基因-1(AEG-1)在恶性胶质瘤中的表达增加，抑制AEG-1可以显著降低恶性胶质瘤细胞的侵袭和迁移特性。AEG-1通过激活核因子-kB信号通路发挥作用。在细胞核中，AEG-1与NF-kB的p65亚基以及CBP相互作用，CBP是一种转录激活剂，可以增强NF-kB的转录活性。因此，AEG-1作为转录的共激活因子发挥作用。AEG-1不包含任何经典的DNA结合域或转录激活域，表明它主要通过与其他蛋白质的相互作用发挥作用。此外，AEG-1还通过激活PI3K/Akt通路保护正常星形胶质细胞免受血清饥饿诱导的凋亡。本建议的长期目标是揭示恶性胶质瘤发生和发展的分子机制，以便利用所获得的信息来开发新的治疗策略，以更有效地治疗恶性弥漫性胶质瘤肿瘤。本研究的近期目标是通过建立星形胶质细胞特异性的AEG-1过表达转基因小鼠来验证AEG-1在体内调控胶质瘤侵袭中的作用，详细阐明AEG-1功能的分子机制，特别是在调节NF-kB和PI3K/Akt活性的背景下，并确定恶性胶质瘤细胞迁移和侵袭所需的关键AEG-1下游基因。我们提出的研究是创新的，因为我们的目标是了解新基因AEG-1的功能，该基因在恶性胶质瘤的进展中发挥重要作用。拟议研究的成功完成将对恶性胶质瘤的发病机制产生新的见解，有可能转化为这种侵袭性和往往致命的癌症的有效治疗方法。公共卫生相关性：侵袭周围正常脑组织是恶性胶质瘤手术切除不彻底的根本原因，从而导致复发和死亡。星形胶质细胞上调基因-1(AEG-1)在恶性胶质瘤中过表达，在调节恶性胶质瘤细胞侵袭特性中起重要作用。本研究旨在了解AEG-1在体外和体内转基因小鼠模型中发挥作用的分子机制，为未来基于AEG-1靶向抑制的恶性胶质瘤新疗法的发展铺平道路。

DESCRIPTION (provided by applicant): Malignant glioma is the most fatal of all brain cancers. The tumor invades into the surrounding tissue thus limiting complete removal by surgical resection resulting in recurrence. Identifying molecules involved in glioma invasion is an important step to develop rationally targeted effective therapies. We have demonstrated that the expression of Astrocyte Elevated Gene-1 (AEG-1) is increased in malignant glioma and inhibition of AEG-1 significantly decreases invasion and migration properties of malignant glioma cells. AEG-1 exerts its function by activating the NF-kB signaling pathway. In the nucleus, AEG-1 interacts with the p65 subunit of NF-kB as well as with CBP, an activator of transcription that augments NF-kB transcriptional activity. Thus AEG-1 functions as a co-activator of transcription. AEG-1 does not contain any classical DNA-binding domain or transcription activation domain indicating that it exerts its effects predominantly by interaction with other proteins. Additionally, AEG-1 also protects normal astrocytes from serum starvation-induced apoptosis by activating the PI3K/Akt pathway. The long-term objective of the present proposal is to unravel the molecular mechanism of malignant glioma generation and progression so that the garnered information might be exploited to develop novel therapeutic strategies for the more effective management of malignant-diffuse glioma tumors. The immediate objectives of the present proposal are to authenticate the role of AEG-1 in in vivo regulation of glioma invasion by developing an astrocyte-specific AEG-1-overexpresing transgenic mouse, elucidate in detail the molecular mechanism of AEG-1 function, especially in the context of regulation of NF-kB and PI3K/Akt activity and identify critical AEG-1-downstream genes required for migration and invasion of malignant glioma cells. Our proposed studies are innovative because we aim at understanding the functions of a novel gene AEG-1 that plays an essential role in malignant glioma progression. Successful completion of the proposed studies will generate novel insights into malignant glioma pathogenesis with potential to translate into an effective therapy for this aggressive and frequently fatal cancer. PUBLIC HEALTH RELEVANCE: Invasion into surrounding normal brain tissue is an underlying cause for incomplete surgical removal of malignant glioma tumors resulting in recurrence and fatality. Astrocyte Elevated Gene-1 (AEG-1) is overexpressed in malignant glioma tumors and plays an essential role in regulating invasive properties of malignant glioma cells. The proposed studies aim at understanding the molecular mechanism of AEG-1 function, both in vitro and in vivo in transgenic mouse models, which will pave the way for the development of future novel therapies of malignant glioma based on targeted inhibition of AEG-1.