The poor prognosis of hepatocellular carcinoma (HCC) was ascribed to metastasis. Targeted therapy aiming at the molecules along the metastatic pathway is a promising therapeutic strategy. Among them, hydrogen peroxide inducible clone-5 (Hic-5) is highlighted. Hic-5, discovered as a reactive oxygen species (ROS)-inducible gene, was identified to be an adaptor protein in focal adhesion and a critical signaling mediator upregulated in various cancers including HCC. Moreover, Hic-5 may regulate epithelial-mesenchymal transition (EMT) transcription factor Snail and its downstream mesenchymal genes including fibronectin and matrix metalloproteinase-9 required for migration and invasion of HCC. However, the comprehensive Hic-5-mediated pathway was not established and whether Hic-5 can be a target for preventing HCC progression has not been validated in vivo. Using whole-transcriptome mRNA sequencing, we found reactive oxygen species modulator (ROMO) and ZNF395 were upregulated by Hic-5 in a patient-derived HCC cell line, HCC372. Whereas ROMO was involved in Hic-5-mediated ROS signaling, ZNF395 locates downstream of Snail for mesenchymal genes expression required for cell migration. Also, ZNF395 but not ROMO was upregulated by Hic-5 for migration in another patient-derived HCC cell line, HCC374. Further, by in vivo knock down of Hic-5 using the Stable Nucleic Acids Lipid nanoparticles (SNALP)-carried Hic-5 siRNA, progression of HCC372 and HCC374 in SCID mice was prevented, coupled with the decrease of the downstream mesenchymal genes. Our study provides the preclinical evidence that targeting Hic-5 is potentially able to prevent the progression of HCCs with Hic-5 overexpression.
Keywords: Hic-5; ZNF395; metastasis; reactive oxygen species modulator; stable nucleic acids lipid nanoparticles.
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