Role of TRIP6 in Malignant Glioma Progression

TRIP6 在恶性胶质瘤进展中的作用

• 批准号: 7827936
• 负责人: FANG-TSYR LIN
• 金额: $ 12.12万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7827936
• 关键词: Actins; Animal Model; Apoptosis; Apoptotic; Binding; Biological; Brain Neoplasms; Cell Adhesion Molecules; Cell Cycle; Cell Cycle Progression; Cell Nucleus; Cell Survival; Cells; Clinical; Complex; Cytoskeletal Modeling; Data; Disease; Disease Progression; Distant; E2F1 gene; Excision; Family member; Focal Adhesions; Future; G1 Phase; Gene Targeting; Genes; Genetic Transcription; Glioblastoma; Glioma; Goals; Imaging technology; In Vitro; LIM Domain; Malignant Glioma; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Neoplasm Metastasis; Nuclear Translocation; Operative Surgical Procedures; Outcome; PI3K/AKT; PTK2 gene; Pathway interactions; Patients; Phase; Phosphorylation; Play; Primary Brain Neoplasms; Production; Protein Dephosphorylation; Proteins; Radiation; Regulation; Reporting; Resistance; Risk; Role; SH2-Binding Motif; SRC gene; Signal Pathway; Signal Transduction; Small Interfering RNA; Thyroid Hormone Receptor; Transcription Factor AP-1; Transcriptional Regulation; Translating; Tumor Cell Invasion; Tumor Suppressor Proteins; Xenograft procedure; alkylglycerophosphoethanolamine phosphodiesterase; base; brain tissue; cancer stem cell; cell growth; cell motility; chemotherapy; design; drug development; effective therapy; human BCAR1 protein; human RIPK1 protein; improved; in vivo; inhibitor/antagonist; migration; molecular marker; mortality; nerve stem cell; new therapeutic target; novel; overexpression; paxillin; prevent; promoter; protein complex; protein protein interaction; public health relevance; rho; rho GTP-Binding Proteins; self-renewal; small molecule; stemness; transcription factor; tumor; tumor growth; tumor progression

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.

描述（由申请人提供）：恶性神经胶质瘤是最常见和致命的原发性脑肿瘤。尽管影像技术的进步和手术切除肿瘤显着降低了恶性胶质瘤的死亡率，但如何增强对放疗和化疗的敏感性，降低肿瘤侵袭和转移的风险仍然是一个巨大的挑战。含有 LIM 结构域的 TRIP6（甲状腺激素受体相互作用蛋白 6）是一种参与细胞运动和转录控制的粘着斑分子。通过多结构域介导的蛋白质-蛋白质相互作用，TRIP6 与焦点复合物的多个成分结合，并以 c-Src 依赖性方式促进 ERK 激活、Rho 信号传导和细胞迁移。此外，TRIP6 能够穿梭至细胞核，作为 NF-κB、AP-1 和 E2F1 的共激活剂，参与抗凋亡和细胞生长相关基因的转录调节。在本提案中，我们提供的新数据表明，抑制 TRIP6 表达可减少多形性胶质母细胞瘤细胞的细胞迁移、增强化疗敏感性并延长细胞周期的 G1 期，表明 TRIP6 在恶性胶质瘤进展中发挥关键作用。由于TRIP6 mRNA和蛋白在多形性胶质母细胞瘤中过度表达，且与疾病进展相关，因此TRIP6可以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 来增强化疗敏感性并降低 GBM 肿瘤侵袭和转移的风险，Aim1 将确定 TRIP6 在化疗耐药、细胞周期进展和细胞迁移中的作用并研究恶性胶质瘤细胞的潜在分子机制。目标 2 将使用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 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为这种德伐他汀疾病设计更有效的疗法。公共健康相关性：含有 LIM 结构域的 TRIP6 在多形性胶质母细胞瘤中过度表达，在胶质瘤肿瘤迁移、化疗耐药和增殖中发挥关键作用。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针对这种破坏性疾病的更有效的疗法。