Expression and Prognostic Implication of the Nuclear Receptors Farnesoid X Receptor and Pregnane X Receptor in Human Cholangiocarcinoma

Abstract

Background/aim: Cumulative evidence reveals the contribution of nuclear receptors in the development and progression of cancers. The present study aimed to investigate the expression of two nuclear receptors, farnesoid X receptor (FXR) and pregnane X receptor (PXR), in cholangiocarcinoma (CCA) tissues and the correlation of their expression with clinicopathological features.

Materials and methods: FXR and PXR expression was evaluated in 111 resected CCA patient samples using immunohistochemistry, and the association of its expression with clinicopathological parameters was analyzed. The effectiveness of the expression of these nuclear receptors in predicting patients' outcomes was also assessed.

Results: FXR and PXR positivity was noted in all examined samples, with their expression predominantly localized in the cytoplasm. Patients with intraductal papillary neoplasm of the bile duct had significantly lower FXR expression (p=0.042). Elevated FXR expression was also significantly associated with lymph node metastasis (p=0.006) and advanced tumor stage (p=0.007). The results of the log-rank test analysis showed that the survival time of the patients was not associated with the expression of these two nuclear receptors. However, the CCA patients presenting low FXR/PXR expression tended to have a longer overall survival (p=0.125).

Conclusion: FXR may contribute to the progression of CCA to more advanced stages. The prognostic significance of FXR and PXR expression appears relevant in CCA. These nuclear receptors may have a function in the prediction and treatment of this deadly disease.

Keywords: FXR; PXR; cholangiocarcinoma; nuclear receptor.

Figure 1

Farnesoid X receptor (FXR) expression in cholangiocarcinoma. The tumor cells invade the hepatic parenchyma (A, H&E). Cytoplasmic expression (B) and cytoplasmic and nuclear expression (C). FXR expression in adjacent normal bile duct (arrow) and hepatocytes (arrowhead) (D). Intensity of FXR expression; score 1+ (E), 2+ (F), and 3+ (G). Original magnification 40×.

Figure 2

Pregnane X receptor (PXR) expression in cholangiocarcinoma. The tumor cells invade the bile duct wall (A, H&E). Diffuse cytoplasmic expression (B) and cytoplasmic granular expression (C). PXR expression in adjacent normal hepatocytes (D). Intensity of PXR expression; score 1+ (E), 2+ (F), and 3+ (G). Original magnification 40×.

Figure 3

Scatter plot graph showing the correlation between the expression of farnesoid X receptor (FXR) and pregnane X receptor (PXR). Significant positive correlation was found between the immunohistochemical score of FXR and PXR (p=0.004).

Figure 4

The association of farnesoid X receptor (FXR) expression with clinicopathological parameters. (A) Mean FXR expression in CCA tissues with the absence of intraductal papillary neoplasm of the bile duct (IPBN) (non-IPBN group) was significantly higher than in CCA tissues with the presence of IPBN (IPBN group) (*p<0.05). (B) There is a significant difference in FXR expression among cholangiocarcinoma (CCA) patients with lymph node involvement compared to those without (*p<0.05). (C) FXR expression in CCA patient tissues at stage I-II was lower than those of stage III-IV patients (*p<0.05).

Figure 5

Correlation between farnesoid X receptor (FXR) and pregnane X receptor (PXR) expression and cumulative survival rate (Kaplan–Meier method). (A) Survival curves of low and high FXR expression groups. (B) Survival curves of low and high PXR expression groups. (C) Survival curves of low FXR/low PXR expression and low FXR/high PXR expression group. (D) Survival curves of high FXR/low PXR expression and high FXR/high PXR expression groups.