Abstract
Target therapy aiming at critical molecules within the metastatic signal pathways is essential for prevention of hepatocellular carcinoma (HCC) progression. 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-β), hepatocyte growth factor (HGF), and reactive oxygen species (ROS). Previous studies implicated Hic-5 cross-talks with the ROS-c-jun N-terminal kinase (JNK) signal cascade in a positive feedback manner. In this report, we addressed this issue in a comprehensive manner. By RNA interference and ectopic Hic-5 expression, we demonstrated Hic-5 was essential for activation of NADPH oxidase and ROS generation leading to activation of downstream JNK and c-jun transcription factor. This was initiated by interaction of Hic-5 with the regulator and adaptor of NADPH oxidase, Rac1 and Traf4, respectively, which may further phosphorylate the nonreceptor tyrosine kinase Pyk2 at Tyr881. On the other hand, promoter activity assay coupled with deletion mapping and site directed mutagenesis strategies demonstrated the distal c-jun and AP4 putative binding regions (943–1126 bp upstream of translational start site) were required for transcriptional activation of Hic-5. Thus Hic-5 was both downstream and upstream of NADPH oxidase-ROS-JNK-c-jun cascade. This signal circuit was essential for regulating the expression of epithelial mesenchymal transition (EMT) factors, such as Snail, Zeb1, E-cadherin, and matrix metalloproteinase 9, involved in HCC cell migration and metastasis. Due to the limited expression of Hic-5 in normal tissue, it can be a promising therapeutic target for preventing HCC metastasis.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common causes of death from cancer worldwide
Quantitative RT-PCR further confirmed the decrease of mRNAs of Snail and matrix metalloproteinase 9 (MMP9) by 50% and 53% (p = 0.01, N = 3), respectively, in HCC413 transfected with Hic-5 siRNA for 48 h (Supplementary Fig. 2A)
Western blots demonstrated MMP9 and Zeb-1 proteins were decreased in HCC413 transfected with Hic-5 siRNA for 24 h by 70–80% compared with those of the cells transfected with control siRNA (Fig. 1e)
Summary
Hepatocellular carcinoma (HCC) is one of the most common causes of death from cancer worldwide. The poor prognosis of HCC is due to high recurrence rate mainly caused by intrahepatic metastasis (about 80%) or extrahepatic metastasis (about 20%)[1]. Tumor metastasis occurs via complicated processes, including epithelial mesenchymal transition (EMT), migration and invasion of primary tumor, followed by intravasation, extravasation, and colonization at the metastatic loci. The tumor microenvironment in HCC contains a lot of metastatic factors, such as hepatocyte growth factor (HGF)[2] and transforming growth factorβ (TGFβ)[3], capable of triggering HCC progression via a lot of molecular pathways. Target therapy aiming at critical signal molecules within these pathways is essential for prevention of HCC metastasis.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
