In digestive system the malignant tumors include pancreatic cancer, gastric cancer, primary liver cancer and others. Hilar cholangiocarcinoma exhibit one of the most malignant phenotype. Despite during several years the diagnostic and therapeutic modalities developed in clinical and basic research, the pathogenesis of hilar cholangiocarcinoma, the changes in the pathological and physiological characteristics of tumors, and the changes of the tumor environment are not completely clear. Factors that are associated with the pathogenesis of hilar cholangiocarcinoma include Calculus of bile duct, congenital cholangiectasis, Chinese liver fluke and primary sclerosing chola. However, the mechanisms that regulate specific signal transduction pathways associated with the malignant phenotype of hilar cholangiocarcinoma are not clear. For example, hilar cholangiocarcinoma may be caused by specific factors that accumulate and interact each other, therefore which can explain the lack of effective treatments. Usually, if the tumor is small or limited to part of the hilar bile duct ,it can be completely resected, patients have a favorable prognosis. However, if the tumor infiltrates surrounding tissues or metastasizes, surgery is impossible. The effects of interventions such as chemotherapy, radiofrequency ablation, radiotherapy, and interventional embolization are limited. Moreover, the rates of recurrence and metastasis are high, and the 5-year survival rate is low. Therefore, more effective diagnostic and therapeutic modalities are urgently required. Although gene therapy is not widely used, it has good prospect. So, we searched for genes involved in the pathogenesis of hilar cholangiocarcinoma that may serve as therapeutic targets[4-6].
FXR usually express on the surface of liver cells and bile duct cells, and its function is to transport bile acid. Therefore, FXR plays an important role in bile-acid excretion, bile-acid concentration stabilization, and the reabsorption process of bile acid enterohepatic circulation[7-10]. We previously found that bile salt export pump (Bsep), a target gene of FXR,expression decreased in hilar cholangiocarcinoma tissues of rats. Therefore, we tried to analyze if the expression levels of FXR, changed similarly in hilar bile duct tissues of rats with hilar cholangiocarcinoma[11-13].
The course of bile acid enterohepatic circulation requires various transporters to interact each other. At first bile acid synthesis by hepatocytes, with the regulation of FXR bile acid is exported to the intestinal tract by the bile salt export pump[14,15]. After bile acid is discharged into the small intestine, approximately 95% of the conjugated bile acid is reabsorbed through the apical sodium-dependent bile acid transporter, ileum bile acid binding protein, and terminal apical sodium-dependent bile acid transporter. sodium/ taurocholate cotransporting polypeptide(Ntcp) mediates approximately 80% of bile acids into liver cells[16,17], which are again secreted into the bile to formate enterohepatic circulation of bile acids[18-20].
If the levels of FXR expression are inappropriate, bile acid secretion and reabsorption disorders may occur, and bile will accumulate in the bile duct[21-23]. So cholesterol and bile pigments may accumulate in bile ducts, leading to the formation of stones. The long-term presence of a calculus in the bile duct is one of possible causes of promoting the growth of hilar cholangiocarcinoma. Therefore, it is important to gain a better understanding of FXR expression in hilar cholangiocarcinoma tissues[24-26].
In the present study, we established a rat model of hilar cholangiocarcinoma. After 6 weeks, hilar cholangiocarcinoma developed only in the experimental group, thereby establishing an experimental model for studying QBC939-induced hilar cholangiocarcinoma.The dietary intake and weights of rats in the experimental group were lower than those of the control group.The frequency of rats with hilar cholangiocarcinoma was 85%. In the experimental group with hilar cholangiocarcinoma, the levels of total cholesterol, total bilirubin, and direct bilirubin were higher than those of the control group. Simultaneously, muddy stones emerged from the bile ducts of rats in experimental group, and the levels of expression of FXR were lower in the rats with hilar cholangiocarcinoma than in those in the control group.Thus, we speculate that if increased quantities of bile acids in bile ducts, the expression of FXR will increase[27,28], which will accelerate the secretion of bile acid to maintain its concentrations. However, in hilar cholangiocarcinoma bile acid secretion is greatly reduced, So bile deposits in the bile duct and potential stone formation. that induces inflammation of the bile duct. Repeated destruction and proliferation of bile duct cells increase the probability of an oncogenic events and the emergence of cells with the malignant phenotype.
There are several problems with the drugs used to treat hilar cholangiocarcinoma.
For example, their use is limited because they do not kill all the tumor cells, require large doses, adversely affect the digestive system, and are poorly tolerated. Drugs in the research and development stages do not directly target the genes that contribute to hilar cholangiocarcinoma. The data presented here may enhance our understanding of the molecular basis of hilar cholangiocarcinoma[29,30]. Moreover, our study illuminates that FXR maybe a target for new and more effective treatment strategies.