| Summary: | 博士 === 國立中興大學 === 生命科學系所 === 99 === Metastasis is the major cause leading to mortality for lung cancer patients. In carcinomas, metastasis is a multiple-step process, the first of which is invasion. Cancer cells acquire their invasive capacity by undergoing phenotypic conversion referred to as epithelial–mesenchymal transition (EMT), which is mediated by various pathway including EGF、Wnt、Src signaling and contributes to metastasis. To obtain the novel metastasis-related genes, we used the microarray-based comparative genomic hybridization and affymetrix gene expression profiles to identify the potential candidates, YWHAZ and HLJ1, respectively. To investigate the roles of YWHAZ and HLJ1 in modulating epithelial-mesenchymal transition and cancer progression, three specific parts are included in this dissertation. In the first part, we investigated the importance of YWHAZ in inducing EMT and invadopodia formation. Our results demonstrated that oncogenic functions of YWHAZ are mediated, at least partly, by prevention of ubiquitination ofβ-catenin. Subsequently, the accumulated β-catenin activates β-catenin/TCF signalling and slug-mediated EMT pathway. On the other hand, YWHAZ associates with Src by its phosphorylation at Y178 and positive regulation of Src-induced podosome rings, causing MMP2 secretion and gelatin degradation. In the second part, we focused on the molecular mechanism of HLJ1 on suppressing migration of lung cancer cells in acidic microenvironment. We not only provide evidence that HLJ1 is a tyrosine phosphoprotein but also illustrate HLJ1 binding to actin cytoskeleton during acidic stress and tyrosine phosphorylation-dependent association with β-actin. Finally, the third part of this dissertation presents a new molecular mechanism in HLJ1-Src complex and illustrates an important role for HLJ1 to inhibit EMT. Our findings revealed that HLJ1 associates with Src and represses its activation as well as downstream signaling, including FAK and β-catenin. Meanwhile, we reveal the critical amino acids in HLJ1 for HLJ1-Src interaction and suppressor characteristic of HLJ1. Taken together, these efforts will enhance our understanding on the impact of YWHAZ and HLJ1 on modulation of EMT and may have important implications for future cancer enhancer and suppressor investigations.
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