Research Papers:

Hydrogen peroxide inducible clone-5 mediates reactive oxygen species signaling for hepatocellular carcinoma progression

Jia-Ru Wu _, Chi-Tan Hu, Ren-In You, Siou-Mei Pan, Chuan-Chu Cheng, Ming-Che Lee, Chao-Chuan Wu, Yao-Jen Chang, Shu-Chuan Lin, Chang–Shan Chen, Teng-Yi Lin and Wen-Sheng Wu

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Oncotarget. 2015; 6:32526-32544. https://doi.org/10.18632/oncotarget.5322

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Jia-Ru Wu1, Chi-Tan Hu3, Ren-In You2, Siou-Mei Pan3, Chuan-Chu Cheng2, Ming-Che Lee4, Chao-Chuan Wu5, Yao-Jen Chang5, Shu-Chuan Lin3, Chang-Shan Chen2, Teng-Yi Lin6, Wen-Sheng Wu2

1Institute of Medical Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan

2Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan

3Research Centre for Hepatology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan

4Department of Surgery, Buddhist Tzu Chi General Hospital, School of Medicine, Tzu Chi University, Hualien, Taiwan

5Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, School of Medicine, Tzu Chi University, Hualien, Taiwan

6Department of Laboratory Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

Correspondence to:

Wen-Sheng Wu, e-mail: [email protected]

Keywords: HGF, paxillin, metastasis, JNK, migration

Received: April 18, 2015     Accepted: September 11, 2015     Published: September 22, 2015


One of the signaling components involved in hepatocellular carcinoma (HCC) progression is the focal adhesion adaptor paxillin. Hydrogen peroxide inducible clone-5 (Hic-5), one of the paralogs of paxillin, 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 metastasis. Hic-5 highly expressed in the patient derived HCCs with high motility such as HCC329 and HCC353 but not in the HCCs with low motility such as HCC340. Blockade of Hic-5 expression prevented constitutive migration of HCC329 and HCC353 and HGF-induced cell migration of HCC340. HCC329Hic-5(-), HCC353Hic-5(-), HCC372Hic-5(-), the HCCs stably depleted of Hic-5, exhibited reduced motility compared with each HCC expressing Scramble shRNA. Moreover, intra/extrahepatic metastasis of HCC329Hic-5(-) in SCID mice greatly decreased compared with HCC329Scramble. On the other hand, ectopic Hic-5 expression in HCC340 promoted its progression. Constitutive and HGF-induced Hic-5 expression in HCCs were suppressed by the reactive oxygen species (ROS) scavengers catalase and dithiotheritol 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 in HCCs. 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 anti-HCC peptide LZ-8 suppressed constitutive Hic-5 expression and JNK phosphorylation. In conclusion, Hic-5 mediates ROS-JNK signaling and may serve as a therapeutic target for prevention of HCC progression.

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