Plasma Bile Acid Profiling and Modulation of Secreted Mucin 5AC in Cholangiocarcinoma

Abstract

Studies investigating the potential role of circulating bile acids (BAs) as diagnostic biomarkers for cholangiocarcinoma (CCA) are sparse and existing data do not adjust for confounding variables. Furthermore, the mechanism by which BAs affect the expression of the oncogenic mucin 5AC (MUC5AC) has never been investigated. We performed a case–control study to characterise the profile of circulating BAs in patients with CCA (n = 68) and benign biliary disease (BBD, n = 48) with a validated liquid chromatography–tandem mass spectrometry technique. Odd ratios (OR) for CCA associations were calculated with multivariable logistic regression models based on a directed acyclic graph structure learning algorithm. The most promising BAs were then tested in an in vitro study to investigate their interplay in modulating MUC5AC expression. The total concentration of BAs was markedly higher in patients with CCA compared with BBD controls and accompanied by a shift in BAs profile toward a higher proportion of primary conjugated BAs (OR = 1.50, CI: 1.14 to 1.96, p = 0.003), especially taurochenodeoxycholic acid (TCDCA, OR = 42.29, CI: 3.54 to 504.63, p = 0.003) after multiple adjustments. Western blot analysis of secreted MUC5AC in human primary cholangiocytes treated with primary conjugated BAs or with TCDCA alone allowed us to identify a novel 230 kDa isoform, possibly representing a post-translationally modified MUC5AC specie.

Association of preoperative elevated lipoprotein (a) with poor survival in patients with biliary tract cancers

“…Biliary tract cancers account for approximately 3% of all gastrointestinal malignancies, and its incidence is increasing globally. 1 Based on their anatomical structure, these cancers encompass gallbladder cancer (GC), intrahepatic cholangiocarcinoma (ICC), or extrahepatic cholangiocarcinoma (ECC). 2 While radical surgical resection is an effective treatment for early biliary tract cancers, for patients with locally advanced or metastatic disease, clinicians may resort to chemotherapy, 3 immunotherapy, 4 and targeted therapy, 5 with a modest 5-year survival rate ranging from 5% to 15%.…”

“…Biliary tract cancers account for approximately 3% of all gastrointestinal malignancies, and its incidence is increasing globally 1 . Based on their anatomical structure, these cancers encompass gallbladder cancer (GC), intrahepatic cholangiocarcinoma (ICC), or extrahepatic cholangiocarcinoma (ECC) 2 .…”