Journal of Nanomedicine & Biotherapeutic Discovery
Open Access

Abstract

Hydrogen peroxide inducible clone-5 mediates positive feedback ROS-JNK-c-jun signaling for HCC progression

Wen-Sheng Wu

The poor prognosis of hepatocellular carcinoma (HCC) is due to high recurrence rate mainly caused by intrahepatic metastasis. Hic-5 (hydrogen peroxide inducible clone-5) which belongs to the paxillin superfamily can be stimulated by a lot of metastatic factors including transforming growth factor (TGFβ) and hepatocyte growth factor (HGF), which further regulate epithelial mesenchymal transition (EMT), migration and invasion. The molecular mechanisms for Hic-5 to trigger EMT and tumor progression appeared to be closely associated with its impact on signal transduction. Our recent report demonstrated that Hic-5 not only can be a poor prognosis marker for HCC but also served as a mediator of the reactive oxygen species (ROS)-c-jun-Nterminal kinase (JNK) signaling pathway for HCC progression. Notably, Hic-5 appeared to locate both upstream and downstream of ROS-JNK cascade. In our recent study, a more comprehensive Hic-5-ROS-JNK positive feedback pathway has been established. Specifically, Hic-5 may interact with regulators of NADPH oxidase such as Rac-1, Traf4 and nonreceptor tyrosine kinase (Pyk2) for activating NADPH oxidase and ROS generation, leading to JNK phosphorylation and transcriptional activation of Hic-5 mediated by c-jun/AP-4. The Hic-5 thus induced in turn re-activates the ROS-JNK signal cascade. This positive feedback circuit is essential for elevating mesenchymal transcriptional factors such as Snail, Zeb1 and matrix degradation enzyme MMP9 and decreasing the epithelial marker E-cadherin (Fig.1). Currently, the missing links in both the upstream and downstream of Hic-5-NADPH oxidase-ROS-JNK-c-jun pathway are being clarified. Moreover, whether knockdown of Hic-5 in vivo may decrease HCC progression in a SCID mice are being investigated. Our study will benefit designing a more effective target therapy aiming at Hic-5 against HCC.

Published Date: 2020-11-30; Received Date: 2020-11-20