# The Nuclear Receptor PXR in Chronic Liver Disease
## 6 PXR and Liver Cancer  
### PXR and Hepatocellular Carcinoma  
Hepatocellular carcinoma (HCC), the most common primary tumor affecting the liver, represents the third cause of cancer-related death in the world. HCC onset and progression can be summarized by the description of the different phases characterizing its development. The \"initiation phase\" consists in DNA damage, due to different causes including exposure to chemical compounds. This leads to aberrant alterations of oncogenes and tumor suppressor genes. In the \"promotion phase\", hepatocytes display a high proliferation rate, while in the last phase, i.e., the \"progression phase\", hepatic cells progress to a neoplastic phenotype, sustaining tumor progression and uncontrolled growth [13]. The pleiotropic effects of PXR in cancer have not been completely unraveled, and controversial observations are reported in the literature in this regard (see [1], Table 4). [PERSON] and collaborators observed that the PXR gene and protein levels were reduced in a mouse model of HCC obtained by DEN treatment, whereas the expression of the two pro-inflammatory cytokines IL-6 and TNF\(\kappa\) was upregulated. Moreover, the stable transfection of HepG2 cell line with PXR reduced cell migration, adhesion, and invasion, thus suggesting that high PXR levels may play an antitumoral role in the liver [91]. At variance, many studies have demonstrated a correlation between PXR activation and hepatocyte proliferation, which could prompt HCC development. In this regard, [PERSON] and colleagues compared mice treated with the PXR activator PCN with mice treated with PCN in combination with the constitutive androstane receptor (CAR) ligand 1,4-bis-[2-(3,5-dichlororyridyloxy)]-benzene (TCPOBOP) [13]. CAR is another transcription factor known to have a crosstalk with PXR and to be activated by xenobiotics, such as phenobarbital \begin{table}
\begin{tabular}{c c c} \hline \hline
**Effect** & **Model** & **Reference** \\ \hline PXR activators inhibit HSC & & \\ differentiation and reduce hepatic & Human myofibroblasts and SJL/J mice & [10] \\ inflammation and fibrosis & & \\ Decrease in PXR expression & Mice treated with thioacetamide or fed & \\  & with a high-fat–cholesterol (HFC) diet & [12] \\ PCN-induced PXR activation decreases & & \\ fibrogenesis by downregulating & & \\ TGF–\(\beta\)1 pathway and HSC & & \\  & transdifferentiation & \\ Decrease in PXR expression in & & \\ end-stage liver disease, correlated with & & \\ the downregulation of GSTA1 and CAR & & \\ Decrease in PXR expression & Patients with viral hepatitis and fibrosis & [88; 89] \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Main studies investigating the involvement of PXR in liver fibrosis. (PB) [13; 92]. The study demonstrated that PXR activation is not able to induce cancerous hepatocytes proliferation without the concomitant activation of CAR, indicating that both receptors are needed for HCC development [13]. According to these authors, PXR enhances the transcriptional activity of CAR, modulating the cell cycle since its activation reduces the expression of cell-cycle suppressor genes (_Cdkn1b, Rbl2, Cdkn1a_), accelerating tumor progression and prompting hepatocytes proliferation. Other in vivo experiments confirm the crosstalk between PXR and other cell-cycle regulators, such as forkhead box proteins (FOXO). In summary, exposure to xenobiotics as environmental pollutants and toxins induces PXR and CAR activation and the consequent hyperproliferation of hepatocytes, thus prompting cancer development. This process is further sustained by PXR activation, by downregulating FOXO-dependent suppressor genes, with an impact on cell cycle [93]. The mutual role of PXR and CAR in hepatic carcinogenesis has been confirmed by [PERSON] and colleagues, who conducted in vivo experiments with PCN and phenobarbital and demonstrated that PXR activation increases the proliferation of hepatocytes and becomes carcinogenic only when PXR activation is concomitant with CAR stimulation [94].