# The Nuclear Receptor PXR in Chronic Liver Disease
## 6 PXR and Liver Cancer
### PXR and Cholangiocarcinoma  
Cholangiocarcinoma (CCA) is a malignancy of the bile duct classified according to the affected anatomical areas in distal CCA (dCCA), intrahepatic CCA (iCCA), and perihilar CCA (pCCA) [98]. In detail, iCCA is situated near the second-order bile ducts, while perihilar and distal CCA are located in the distal extremities of the liver. Since pCCA originates from the left or right hepatic duct and dCCA interests the bile duct, they might be considered as extrahepatic CCAs (eCCA) [99]. These malignancies are often characterized by high and variable mortality rates, depending on gender, genetic mutations, and geographical origins of the patients, since they more severely affect patients of the Eastern countries [98; 100]. Interestingly, CCA has been found to be widely spread in the northeastern region of Thailand, hypothesizing that _Opistlorchis viverrini_ infection might represent an important risk factor for the development of this cancer [100]. PSC represents another risk factor because biliary inflammation and bile flow impairment lead to an overexposure of cholangiocarcinomaytes to toxic BAs, causing a progressive destruction of intrahepatic bile ducts [101]. Chronic viral diseases such as hepatitis B and C can turn into liver cirrhosis, commonly characterized by an insufficient bile acid excretion and an increase in proinflammatory factors, attracting additional bacterial contaminants to the biliary traits [102]. Furthermore, it has also been demonstrated that metabolic dysfunctions, including type I and II diabetes and NAFLD, increase the risk of both intra and extrahepatic CCA. The proposed mechanism relies on the fact that an excess of adipose tissue contributes to insulin resistance and type II diabetes, leading to a compensatory hyperinsulinemia and an enhanced production of the insulin-growth factor-1 (IGF-1), whose signaling pathway increases cell proliferation. To strengthen this association, a study performed by [PERSON] and colleagues found that CCA patients express significantly higher levels of IGF-1 compared with healthy livers [102]. Hepatic inflammation and cirrhosis of NAFLD patients have been associated with CCA development since it has been demonstrated that an increase in pro-inflammatory signaling molecules induces the growth of cholangiocarcinomaytes and DNA damage [103]. Regardless of the etiology, CCA is characterized by a severe transformation of cholangiocarcinomaytes, together with high concentrations of conjugated BAs in the liver and in the blood [100; 104]. It has been hypothesized that conjugated BAs may play a key role in the development of CCA since the bile of CCA patients was found to be enriched of taurine and glycine-conjugated BAs [101]. This hypothesis has been strengthened by in vitro and in vivo studies, respectively conducted on QBC939 CCA cells and xenograft mouse models, demonstrating that conjugated BAs were able to increase the growth of tumoral cells, whereas free BAs exert beneficial roles by inhibiting tumor development [101]. Despite the well-known relationship between BAs and NRs, which have been described in detail above, only a few studies attempted to address this issue in CCA. The role of the PXR partner RXR\(\alpha\) has been investigated by [PERSON] and colleagues, who reported its overexpression in the cell cytoplasm of human CCA tissues and in CCA cell lines. For the first time, a role for RXR\(\alpha\) has been proposed in CCA growth, by the activation of the Wtn/\(\beta\)-catenin pathway, enhancing the activity of the cell-cycle regulator cyclin D1. Moreover, it has been demonstrated that the knockdown of RXR\(\alpha\) decreased the survival of CCA cells by reducing the expression of two G1/S regulators, such as cyclin D1 and E, leading to cell-cycle arrest [105]. Thus, targeting RXR\(\alpha\) might be a strategy for the development of new therapeutic agents against CCA. The NR FXR might also be a promising pharmacological target for CCA therapy.