Role of TRIP6 in Malignant Glioma Progression

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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.