| Summary: | 博士 === 國立東華大學 === 生命科學系 === 105 === Glioblastoma (GBM) is the most common and most aggressive brain malignant tumor. Due to the high recurrence rate and poor prognosis of GBM, the patients’ median survival rate is 12-15 months. Most researchers suggest that the recurrence is due to the presence of cancer stem cells (CSCs), which has radioresistant, chemoresistant, highly invasive, self-renewal and tumorigenic potentials. Axl receptor tyrosine kinase has been shown to be linked to various high-grade cancers, and Axl is also correlated with tumor growth, angiogenesis, and tumor cell invasion. In our previous studies, we demonstrated that EF-001 could inhibit GBM cell migration and invasion in vitro. In this study, it showed that EF-001 not only inhibited GBM tumor growth, prolonged the survival rate in an orthotopic tumor model, but inhibited tumor cell invasion in vivo also. Furthermore, we used EF-001 to assess the anti CD133+ cell potential, and then tried to find out the associated gene regulation in invasion and migration. Our results indicated that EF-001 could induce CD133+ cell apoptosis through G2 / M phase arrest, and reduce the colony formation ability of CD133+ cell. Moreover, we found that EF-001 could inhibit the expression of CD133+ cells associated genes, including CD133 and enhancer of zeste homolog 2 (EZH2), which are involved in CSCs maintenance, growth and colony formation ability. Also, EF-001 reduced the stemness related genes of CD133+ cells as well. In addition, EF-001 inhibited the expression of Axl in a dose dependent manner and reduced the epithelial-to-mesenchymal transition (EMT), migratory and invasive capabilities of GBM CD133+ cells. EMT is related to epithelial cells in the invasive migratory mesenchymal cells that underlie cancer progression. When tumor cells are under EMT process, it will increase the CSCs stemness related gene expression and induce CSCs activation. Finally, we used the overexpression of Axl, EZH2 and Sox2 in GBM CD133+ cells to prove that Axl and EZH2 genes are crucial target in the inhibition of GBM CD133+ cells EMT, migration, and invasion. We found that Axl/EZH2, not Sox2, might be the key regulator in tumor invasion, migration and EMT. The results of this study may contribute to the development of EF-001 for clinical applications in the future.
|
|---|
