Role of TRIP6 in Malignant Glioma Progression

描述（申请人提供）：恶性胶质瘤是最常见、最致命的原发性脑肿瘤。尽管影像学技术的进步和手术切除肿瘤显著降低了恶性胶质瘤的死亡率，但如何提高其对放化疗的敏感性，降低肿瘤侵袭转移的风险仍然是一个很大的挑战。LIM结构域含有甲状腺激素受体相互作用蛋白6 (TRIP6)，是一种参与细胞运动和转录控制的黏附分子。通过多结构域介导的蛋白-蛋白相互作用，TRIP6与局灶复合物的几种组分结合，并以c- src依赖的方式促进ERK激活、Rho信号传导和细胞迁移。此外，TRIP6能够穿梭到细胞核中作为NF-？B、AP-1和E2F1参与抗凋亡和细胞生长相关基因的转录调控。在这篇论文中，我们提供了新的数据表明，在胶质母细胞瘤多形性细胞中，抑制TRIP6的表达可以减少细胞迁移，增强化学敏感性，延长细胞周期的G1期，这表明TRIP6在恶性胶质瘤的进展中起着关键作用。由于多形性胶质母细胞瘤中TRIP6 mRNA和蛋白水平的过表达与疾病进展相关，因此TRIP6可能成为恶性胶质瘤治疗的新靶点。为了研究TRIP6是否可以作为GMB进展的分子标志物，并确定我们是否可以靶向TRIP6来增强化疗敏感性，降低GBM肿瘤侵袭和转移的风险，Aim1将确定TRIP6在恶性胶质瘤细胞中化疗耐药、细胞周期进展和细胞迁移中的作用，并研究其潜在的分子机制。目的2将通过异种移植动物模型研究TRIP6在GBM肿瘤增殖、侵袭和转移中的生物学作用，并确定抑制TRIP6的表达是否可以增强体内化疗敏感性。这项研究的理解将有助于设计更有效的治疗这种毁灭性疾病的方法。公共卫生相关性：含有LIM结构域的TRIP6在多形性胶质母细胞瘤中过表达，并在胶质瘤肿瘤迁移、化疗耐药和增殖中起关键作用。该项目的目标是了解培养的神经胶质瘤细胞和动物模型中的分子机制，以便将这种理解转化为更有效的治疗这种毁灭性疾病的方法。

DESCRIPTION (provided by applicant): Malignant glioma is the most common and lethal primary brain tumor. Despite the improvement of imaging technology and surgical removal of the tumors significantly reduces the mortality of malignant glioma, how to enhance the sensitivity to radiation and chemotherapy, and reduce the risk of tumor invasion and metastasis still remains a big challenge. The LIM domain-containing TRIP6 (Thyroid Hormone Receptor-Interacting Protein 6) is a focal adhesion molecule involved in cell motility and transcriptional control. Through the multidomain-mediated protein-protein interactions, TRIP6 binds to several components of focal complexes and promotes ERK activation, Rho signaling and cell migration in a c-Src-dependent manner. In addition, TRIP6 is capable of shuttling to the nucleus to serve as a coactivator of NF-?B, AP-1 and E2F1 in the transcriptional regulation of genes involved in anti-apoptosis and cell growth. In this proposal, we provide novel data showing that inhibition of TRIP6 expression reduces cell migration, enhances chemosensitivity and prolongs G1 phase of the cell cycle in glioblastoma multiforme cells, suggesting a critical role for TRIP6 in malignant glioma progression. As the levels of TRIP6 mRNA and proteins are overexpressed in glioblastoma multiforme, which is correlated to the disease progression, TRIP6 can be a novel therapeutic target for malignant glioma treatment. To investigate if TRIP6 can serve as a molecular marker in GMB progression and determine if we can target TRIP6 to enhance chemosensitivity and reduce the risk of GBM tumor invasion and metastasis, Aim1 will determine the roles of TRIP6 in chemoresistance, cell cycle progression and cell migration and investigate the underlying molecular mechanisms in malignant glioma cells. Aim 2 will study the biological roles of TRIP6 in GBM tumor proliferation, invasion and metastasis using a xenograft animal model and determine if inhibition of TRIP6 expression can enhance chemosensitivity in vivo. The understanding from this study will help to design more effective therapies for this devastatin disease. PUBLIC HEALTH RELEVANCE: The LIM domain-containing TRIP6 is overexpressed in glioblastoma multiforme and plays a critical role in glioma tumor migration, chemoresistance and proliferation. The goal of this project is to understand the molecular mechanisms in cultured glioma cells and in an animal model in order to translate this understanding into more effective therapies for this devastating disease.