Abstract
Deregulated expression of Notch receptors and abnormal activity of Notch signaling have been observed in a growing number of malignant tumors, however, the expression and activity of Notch in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and their relationship with HBV X protein (HBx) are still not fully elucidated. To address this, we examined the overall expression of Notch receptors in HBV-associated HCC tissues, analyzed their relationship with HBx, and further investigated the role of Notch signaling in HBx stable transfected HepG2 cells (HepG2X). The results showed that Notch signaling could be activated by HBx in HepG2 cells. The expression of cytoplasmic Notch1 or nuclear Notch4 was correlated with the expression of HBx in HBV-associated HCC tissues. The expression of cytoplasmic Notch1 or nuclear Notch4 could also be upregulated by HBx in HepG2X cells. The upregulation of Notch1 by HBx was through p38 MAPK pathway. Moreover, HBx was found to directly interact with Notch1, whereas, not with Notch4 in HepG2X cells. Suppression of Notch signaling by γ-secretase inhibitor (GSI) decreased cell growth, blocked cell cycle progression and induced cell apoptosis in HepG2X cells. The present study indicates that HBx activates Notch signaling by its effects on Notch1 and Notch4, and therefore, recruits Notch signaling as a downstream pathway contributing to its carcinogenic role in HBV-associated HCC.
Highlights
Notch signaling controls various biological events and is vital for many types of cell fate determination in embryonic development
hepatocellular carcinoma (HCC) tissue samples were obtained from 44 patients with hepatitis B virus (HBV) infection who received surgical resection at Xijing Hospital of the Fourth Military Medical University from 2002 to 2004 with informed consents of the the patients and with the approval of the human research committee of the university and Wuhan General Hospital. pcDNA3-HBV X protein (HBx) was constructed by inserting a wild-type HBx cDNA fragment into pcDNA3 (Invitrogen, Carlsbad, CA, USA). pcDNA3 stable transfected HepG2 cells (HepG2-pc) and HepG2X cells were established in our perious study [20]
HBx upregulates the expression of Notch1 through p38 MAPK pathway and activates Notch4 in HBV-associated HCC tissues and HepG2X cells
Summary
Notch signaling controls various biological events and is vital for many types of cell fate determination in embryonic development. Four Notch receptors (Notch1-4) and two groups of ligands, Jagged and Delta-like, have been identified in mammals [1]. The activation of Notch signaling is initialized by the binding of Notch receptors and ligands, which leads to Overexpression of Notch is identified as a significant and independent prognostic factor for esophageal squamous cell cancer [9]
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