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, Wen Sheng Wu

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)32526-32544
Number of pages19
JournalOncotarget
Volume6
Issue number32
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • HGF
  • JNK
  • Metastasis
  • Migration
  • Paxillin

ASJC Scopus subject areas

  • Oncology

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