Role of PXR in Hepatic Cancer: Its Influences on Liver Detoxification Capacity and Cancer Progression

Abstract

The role of nuclear receptor PXR in detoxification and clearance of xenobiotics and endobiotics is well-established. However, its projected role in hepatic cancer is rather illusive where its expression is reported altered in different cancers depending on the tissue-type and microenvironment. The expression of PXR, its target genes and their biological or clinical significance have not been examined in hepatic cancer. In the present study, by generating DEN-induced hepatic cancer in mice, we report that the expression of PXR and its target genes CYP3A11 and GSTa2 are down-regulated implying impairment of hepatic detoxification capacity. A higher state of inflammation was observed in liver cancer tissues as evident from upregulation of inflammatory cytokines IL-6 and TNF-α along with NF-κB and STAT3. Our data in mouse model suggested a negative correlation between down-regulation of PXR and its target genes with that of higher expression of inflammatory proteins (like IL-6, TNF-α, NF-κB). In conjunction, our findings with relevant cell culture based assays showed that higher expression of PXR is involved in reduction of tumorigenic potential in hepatic cancer. Overall, the findings suggest that inflammation influences the expression of hepatic proteins important in drug metabolism while higher PXR level reduces tumorigenic potential in hepatic cancer.

Non-coding RNAs: Emerging Regulators of Sorafenib Resistance in Hepatocellular Carcinoma

“…The transcription product of MDR1 is p-gp, which is an energy-dependent “drug pump” and energy-dependent transporter that can accelerate the clearance of antitumor drugs and induce drug resistance. MiR-140-3p targets pregnenolone X receptor (PXR), which can transfer a variety of different compounds out of cells (75), thus increasing intracellular anti-tumor drug concentration including sorafenib by down-regulation of the expression of drug-resistance-related genes (43). Similarly, miR-379 could provoke sorafenib resistance through increasing the expression of multi drug resistant protein (MRP2), which facilitates the anti-tumor drug transport and contributes to sorafenib resistance (76).…”

Phosphorylation Modulates the Coregulatory Protein Exchange of the Nuclear Receptor Pregnane X Receptor

“…In fact, patients suffering from irritable bowel-syndrome can be treated with a gut-specific PXR agonist, rifaximin, to reduce the inflammatory symptoms associated with this disease (Cheng et al, 2010). PXR activation is important in other human diseases to include inflammatory liver disease (Sun et al, 2015), inflammatory bowel disease (Cheng et al, 2012;Cheng et al, 2010;Shah et al, 2007), intra-hepatic cholestasis (Geenes et al, 2011;Goodwin et al, 2003;Kakizaki et al, 2011;Kakizaki et al, 2009;Xie et al, 2001), Type 2 diabetes (Hukkanen et al, 2014), and numerous cancers (Kotiya et al, 2016;Wen et al, 2018). Therefore, understanding the precise molecular mechanisms that regulate PXR biology is critical in developing new therapeutic strategies to alter the course of these diseases.…”

Interaction of Hepatitis B Virus X Protein with the Pregnane X Receptor Enhances the Synergistic Effects of Aflatoxin B1 and Hepatitis B Virus on Promoting Hepatocarcinogenesis

“…The pregnane X receptor (PXR) is a ligand-dependent steroid and xenobiotic receptor that is responsible for the metabolic activation or detoxification of several carcinogens, and may play various roles in hepatocellular carcinogenesis. 9 , 10 The metabolism of AFB1 in vivo is closely related to PXR, cytochrome P450 3A4 (CYP3A4), and glutathione S-transferase Mu 1 (GSTM1). 11 HBV X protein (HBx) is considered a key regulator in HCC, due to its capacity to function as a deregulated transcriptional activator.…”