Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein–induced hepatocarcinogenesis

Abstract

Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) is a HBV protein that has multiple cellular functions, but its role in HCC pathogenesis has been controversial. The farnesoid X receptor (FXR) is a nuclear receptor known to have activities in anti-inflammation and inhibition of hepatocarcinogenesis. However, whether or how FXR can impact HBV/HBx-induced hepatocarcinogenesis remains unclear. In this study, we showed that HBx can interact with FXR and function as a co-activator of FXR. Expression of HBx in vivo enhanced FXR responsive gene regulation. HBx also increased the transcriptional activity of FXR in luciferase reporter gene assay. The HBx-FXR interaction was confirmed by co-immunoprecipitation and GST-pull down assays, and the FXR AF-1 domain was mapped to bind to the third α helix in the C-terminal of HBx. We also found that the C-terminal truncated variants of HBx, which were found in clinical HCC, were not effective in transactivating FXR. Interestingly, recruitment of the full-length HBx, but not the C-terminal truncated HBx, enhanced the binding of FXR to its response element. In vivo, FXR ablation markedly sensitized mice to HBx-induced hepatocarcinogenesis. Conclusions We propose that transactivation of FXR by the full-length HBx may represent a protective mechanism to inhibit HCC, and this inhibition may have been compromised upon the appearance of the C-terminal truncated HBx, or when the expression and/or activity of FXR is decreased.

Defining the relationship between farsenoid X receptor, hepatitis B virus X protein and hepatocellular carcinoma: It's complicated

“…The finding that HBx is a modulator of HBV‐associated HCC has been demonstrated in numerous studies; however, the concept that HBx‐induced FXR activation decreases tumor incidence is innovative. In this article, Niu et al demonstrate that full‐length HBx behaves as a transactivator of FXR that, when activated, decreases HCC development . The investigators elegantly demonstrate that full‐length HBx enhances FXR binding to its response elements, thereby increasing FXR transcriptional activity and target gene expression.…”

Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development

“…Abnormalities in BA metabolism, such as increased TCA, and disruption of FXR signaling have been observed in HCC in humans and rodents . Indeed, FXR activity may suppress HCC, and hepatic tumors spontaneously develop in Fxr ‐null mice .…”

RARβ acts as both an upstream regulator and downstream effector of miR‐22 , which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells

“…The p53 binding site (59-GGGCAGGTCTCCGGCTTG-CCC-39; the consensus half-sites are underlined) is located at 23345 to 23325 bp in the upstream of miR-22 (1), whereas the VDR binding site remains to be uncovered (14). The interaction among these transcriptional factors warrants further investigation because these transcriptional factors have known cancer protective properties (37)(38)(39)(40)(41)(42)(43). Together, transcriptional regulation appears to be an important pathway for miR-22 expression.…”