HBx induces the proliferation of hepatocellular carcinoma cells via AP1 over-expressed as a result of ER stress

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and chronic hepatitis B virus (HBV) infection is the most common risk factor for HCC. The HBV proteins can induce oncogenic or synergy effects with a hyperproliferative response on transformation into HCC. CREBH (cAMP-responsive, element-binding protein H), activated by stress in the endoplasmic reticulum (ER), is an ER-resident transmembrane bZIP (basic leucine zipper) transcription factor that is specifically expressed in the liver. In the present study, we address the role played by CREBH activated by ER stress in HBV-induced hepatic cell proliferation. We confirmed CREBH activation by ER stress and showed that it occurred as a result of/via hepatitis B virus X (HBx)-induced ER stress. CREBH activated by HBx increased the expression of AP-1 target genes through c-Jun induction. Under pathological conditions such as liver damage or liver regeneration, activated CREBH may have an important role to play in hepatic inflammation and cell proliferation, as an insulin receptor with dual functions under these conditions. We showed that CREBH activated by HBx interacted with HBx protein, leading to a synergistic effect on the expression of AP-1 target genes and the proliferation of HCC cells and mouse primary hepatocytes. In conclusion, in HBV-infected hepatic cells or patients with chronic HBV, CREBH may induce proliferation of hepatic cells in co-operation with HBx, resulting in HCC.

Deregulation of the Notch pathway as a common road in viral carcinogenesis

“…The HBx protein has been associated with hepatocellular carcinogenesis because it sustains HBV replication, 71 interacts and inhibits p53 tumor suppressor, increases telomerase reverse transcriptase (TERT) expression, 72 and promotes invasiveness and metastasis in hepatitis B virus-related HCC. 73,74 HBx does not directly bind to DNA, but regulates transcription factors such as NF-κB), 75 the activator protein 1 (AP-1), 76 cAMP response element-binding protein (CREB), 46 and the coactivator CPB/p300, through which it could upregulate NOTCH target genes, but this still requires further validation ( Figure 3A).…”

“…HBx does not directly bind to DNA, but regulates transcription factors such as NF‐κB), the activator protein 1 (AP‐1), cAMP response element‐binding protein (CREB), and the coactivator CPB/p300, through which it could upregulate NOTCH target genes, but this still requires further validation (Figure A).…”

Hepatitis B virus X protein in liver tumor microenvironment

“…These changes may explain the abnormal energy metabolism of tumor cells, the increase of ROS in the tumor microenvironment, the invasion and metastasis of tumor cells, and the resistance to cell death evident in HBV-HCC. Within the endoplasmic reticulum, HBx maintains chronic liver inflammation and proliferation by inducing endoplasmic reticulum stress [7, 61]. Reportedly, HBx also colocalizes with the proteasome and interacts specifically with a novel subunit of the proteasome complex (XAPC7) that is involved in protein degradation; HBx is thought to exert its various functions through the regulation of this process [62, 63].…”

“…HBx regulates the biological behavior of tumor cells through its transcriptional regulation and transactivation activities. Reportedly, HBx promotes hepatoma cell proliferation via the activation of cellular signaling pathways, dysregulation of cell-cycle checkpoint controls, and regulation of non-coding RNAs and transcription factors [5, 7, 69]. The impact of HBx expression on cellular apoptosis has also been analyzed.…”

“…Hepatitis B virus X protein (HBx), a multifunctional viral protein encoded by HBV, is considered to be one of the most important determinants of the pathology of HBV-related HCC (HBV-HCC). An accumulating body of evidence has suggested that HBx exerts its carcinogenic effects by activating a variety of cellular signaling pathways thereby controlling the cell cycle, proliferation, and apoptosis [5–7]. …”