| Summary: | 碩士 === 慈濟大學 === 醫學生物技術碩士班 === 107 === The poor prognosis of HCC is due to high recurrence rate mainly caused by intrahepatic metastasis or extrahepatic metastasis. The tumor microenvironment of HCC contains a lot of metastatic factors including hepatocyte growth factor (HGF), which are capable of triggering HCC metastatic phenotypes including epithelial to mesenchymal transition (EMT), migration and invasion. Therefore, it is promising to prevent HCC metastasis by targeting the critical molecules within the signal pathway triggered by the metastatic factors. Hic-5 (hydrogen peroxide inducible clone-5) which belongs to the paxillin superfamily, can be stimulated by a lot of metastatic factors such as transforming growth factor (TGF-) and HGF. Previous studies in our lab suggested Hic-5 interacts with the reactive oxygen species (ROS)-c-jun N-terminal kinase (JNK) signal cascade. Further, We and the colleagues in our lab established the Hic-5 mediated positive feedback signal circuit in a comprehensive manner. In my experiments, by RNA interference and ectopic Hic-5 expression, We demonstrated Hic-5 was essential for activation of JNK and c-jun transcription factor. Hic-5 was also required for the phosphorylation (at Tyr881) of the nonreceptor tyrosine kinase Pyk2, one of the regulator of NADPH oxidase, which is responsible for ROS generation. On the other hand, Hic-5 expression can be prevented by ROS scavenger and inhibitors of JNK and siRNA of c-jun. Thus Hic-5 is both downstream and upstream of ROS-JNK-c-jun cascade. Moreover, this signal circuit was essential for regulation of the expression of EMT markers such as Snail, Zeb1, E-cadherin and matrix metalloproteinase-9. In summary, Hic-5 can be located both upstream and downstream of NADPH oxidase-ROS-JNK-c-jun cascade, therefore, a positive feedback signal circuit can be established for regulating the expressions of EMT markers and HCC progression.
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