Hepatitis B Virus X Protein Drives Multiple Cross-Talk Cascade Loops Involving NF-κB, 5-LOX, OPN and Capn4 to Promote Cell Migration

Abstract

Hepatitis B virus X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). However, the mechanism remains unclear. Recently, we have reported that HBx promotes hepatoma cell migration through the upregulation of calpain small subunit 1 (Capn4). In addition, several reports have revealed that osteopontin (OPN) plays important roles in tumor cell migration. In this study, we investigated the signaling pathways involving the promotion of cell migration mediated by HBx. We report that HBx stimulates several factors in a network manner to promote hepatoma cell migration. We showed that HBx was able to upregulate the expression of osteopontin (OPN) through 5-lipoxygenase (5-LOX) in HepG2-X/H7402-X (stable HBx-transfected cells) cells. Furthermore, we identified that HBx could increase the expression of 5-LOX through nuclear factor-κB (NF-κB). We also found that OPN could upregulate Capn4 through NF-κB. Interestingly, we showed that Capn4 was able to upregulate OPN through NF-κB in a positive feedback manner, suggesting that the OPN and Capn4 proteins involving cell migration affect each other in a network through NF-κB. Importantly, NF-κB plays a crucial role in the regulation of 5-LOX, OPN and Capn4. Thus, we conclude that HBx drives multiple cross-talk cascade loops involving NF-κB, 5-LOX, OPN and Capn4 to promote cell migration. This finding provides new insight into the mechanism involving the promotion of cell migration by HBx.

Characterization of metastatic tumor antigen 1 and its interaction with hepatitis B virus X protein in NF-κB signaling and tumor progression in a woodchuck hepatocellular carcinoma model

“…The activation of NF-κB pathways by HBx is involved in promoting invasion and metastasis in HCC cells [21]. Therefore, we examined whether wk-MTA1 overexpression could also enhance WHx-mediated migration and invasion.…”

The hepatitis B virus X protein promotes pancreatic cancer through modulation of the PI3K/AKT signaling pathway

“…HBx has been shown to activate multiple pathways to promote the degradation of the cellular matrix and decrease intercellular adhesion of liver cells. This leads to increased capacity for cell migration, demonstrating the important role of HBx in liver cancer metastasis [39]. We therefore, hypothesized that HBx could play a similar role if HBV indeed promotes PDAC.…”

Capn4 Enhances Osteopontin Expression through Activation of the Wnt/β-Catenin Pathway to Promote Epithelial Ovarian Carcinoma Metastasis

“…Zhang et al reported that OPN and Capn4 proteins are involved in cell migration and affect each other in a network [16]. Therefore, we speculated that OPN might be involved in the Capn4-mediated pathobiological functions in EOC.…”

“…Rosen et al also reported that OPN can be used as a potential marker that might complement the effectiveness of CA125 as a typical marker in ovarian carcinoma [26]. Other studies have shown that OPN and Capn4 proteins are involved in cell migration, and affect each other in a network through interactions with NF-κB [16]. Accumulating evidence also indicates that OPN mediates cancer cell adhesion, migration, and proliferation through interaction with its receptor, integrin [22, 27, 28].…”