Discovery of glycocholic acid and taurochenodeoxycholic acid as phenotypic biomarkers in cholangiocarcinoma

Abstract

Although several biomarkers can be used to distinguish cholangiocarcinoma (CCA) from healthy controls, differentiating the disease from benign biliary disease (BBD) or pancreatic cancer (PC) is a challenge. CCA biomarkers are associated with low specificity or have not been validated in relation to the biological effects of CCA. In this study, we quantitatively analyzed 15 biliary bile acids in CCA (n = 30), BBD (n = 57) and PC (n = 17) patients and discovered glycocholic acid (GCA) and taurochenodeoxycholic acid (TCDCA) as specific CCA biomarkers. Firstly, we showed that the average concentration of total biliary bile acids in CCA patients was quantitatively less than in other patient groups. In addition, the average composition ratio of primary bile acids and conjugated bile acids in CCA patients was the highest in all patient groups. The average composition ratio of GCA (35.6%) in CCA patients was significantly higher than in other patient groups. Conversely, the average composition ratio of TCDCA (13.8%) in CCA patients was significantly lower in all patient groups. To verify the biological effects of GCA and TCDCA, we analyzed the gene expression of bile acid receptors associated with the development of CCA in a CCA cell line. The gene expression of transmembrane G protein coupled receptor (TGR5) and sphingosine 1-phosphate receptor 2 (S1PR2) in CCA cells treated with GCA was 8.6-fold and 3.4-fold higher compared with control (untreated with bile acids), respectively. Gene expression of TGR5 and S1PR2 in TCDCA-treated cells was not significantly different from the control. Taken together, our study identified GCA and TCDCA as phenotype-specific biomarkers for CCA.

Biliary Microbiota and Bile Acid Composition in Cholelithiasis

“…Other measured BAs amount to 9% of total concentration. The high abundance of GCA, GCDCA, and TCDCA in the total bile composition of patients with cholelithiasis was consistent with the results reported for patients with benign biliary disease[23].…”

Multiple-biological matrices metabolomics identified new metabolite biomarkers for the precise diagnosis of pancreatic cancer and associated tissue metastasis

“…Glycocholic acid is a secondary bile acid, and particularly high levels of bile acids have been implicated in the pathogenesis of liver diseases 19 . One study suggested that glycocholic acid and taurochenodeoxycholic acid 18 can be used as phenotypic biomarkers in cholangiocarcinoma 20 . In this study, glycocholic acid in plasma was observed to be positively correlated with pancreatic cancer, suggesting that bile acids might also be closely associated with pancreatic cancer.…”

“…Therefore, our data reveal that the strong correlation between According to the Warburg effect 34 , most cancer cells employ aerobic glycolysis rather than oxidative phosphorylation to synthesize energy 35 . Proliferating cells divert glucose metabolites into anabolic processes, while glutamine is provided as a carbon 20 source for the TCA cycle 36 . Succinate, as an important intermediate of the TCA cycle, is also intertwined with metabolites of the glutamine metabolic pathway and plays a crucial role in tumourigenesis 37 .…”

Diagnosis of hepatocellular carcinoma using a novel anti‑glycocholic acid monoclonal antibody‑based method

“…A number of studies have indicated that GCA, as a clinical marker to detect liver diseases including HCC, chronic active hepatitis, chronic active hepatitis and chronic active hepatitis (40), has numerous advantages compared with the traditional liver function tests, including alanine aminotransferase, aspartate transaminase and gamma-glutamyltranspeptidase (41,42). Therefore, GCA analysis can provide the basic information for diagnosis, treatment and prognosis of liver diseases, various biliary system diseases, including cholangiocarcinoma (43), intrahepatic cholestasis and alcoholic liver injury (39,44). HCC has a high morbidity and mortality rate.…”