Hydrogen Peroxide Inducible Clone-5 Mediates Reactive Oxygen Species Signaling for Hepatocellular Carcinoma Progression

• Main Authors: Jia-Ru Wu, 吳家如
• Other Authors: Wen-Sheng Wu
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/16350184329297817993

博士 === 慈濟大學 === 醫學科學研究所 === 104 === Hepatocellular carcinoma (HCC) often resulted in death around the world because of its high recurrent rate mainly due to metastasis. In order to develop targeting therapy against HCC, the relevant molecular pathways need to be delineated. It is well known that the focal adhesion adaptor Paxillin is closely associated with HCC progression. In the initial screening we found phosphorylated Paxillin (p-Tyr31) was increased in clinical HCC tissues. Surprisingly, we found hydrogen peroxide inducible clone-5 (Hic-5), one of the paralog of Paxillin, was also elevated in tumor tissue. Hic-5 exhibits many biological functions distinct from paxillin, but may cooperate with paxillin to trigger tumor progression. Screening of Hic-5 in 145 surgical HCCs demonstrated overexpression of Hic-5 correlated well with intra- and extra-hepatic metastatic. Also, Hic-5 highly expressed in the patient derived HCC cell line with high motility such as HCC329 and HCC353 but not in the HCCs with low motility such as HCC340. When Hic-5 expression was depleted, migratory ability of HCC329 and HCC353 or HGF-induced cell migration of HCC340 were prevented. The HCCs stably depleted of Hic-5 such as HCC329Hic-5(-), HCC353Hic-5(-), and HCC372Hic-5(-) exhibited reduced motility compared with each HCC expressing Scramble shRNA. Also, intra/extrahepatic metastasis of HCC329Hic-5(-) in SCID mice greatly decreased compared with HCC329Scramble. On the other hand, ectopic Hic-5 expression in HCC340 promotes its progression. Furthermore, we found constitutive and HGF-induced Hic-5 expression in HCCs could be suppressed by reactive oxygen species (ROS) scavengers such as catalase and dithiotheritol (DTT) and c-Jun N-terminal kinase (JNK) inhibitor SP600125. On the contrary, depletion of Hic-5 blocked constitutive and HGF-induced ROS generation and JNK phosphorylation. Also, ectopic expression of Hic-5 enhanced ROS generation and JNK phosphorylation. These highlighted that Hic-5 plays a central role in the positive feedback ROS-JNK signal cascade. Finally, the Chinese herbal derived peptide LZ-8 also suppressed constitutive and HGF-induced Hic-5 expression and JNK activation in HCC cell lines. In conclusion, Hic-5 mediates ROS-JNK signaling and may serve as a therapeutic target for prevention of HCC progression.