Dataset Information

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.

SUBMITTER: Danese E

PROVIDER: S-EPMC10454108 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Danese Elisa E Lievens Patricia M-J PM Padoan Andrea A Peserico Denise D Galavotti Roberta R Negrini Davide D Gelati Matteo M Conci Simone S Ruzzenente Andrea A Salvagno Gian Luca GL Lippi Giuseppe G

International journal of molecular sciences 20230814 16

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 (<i>n</i> = 68) and benign biliary disease (BBD, <i>n</i> = 48) with a val ...[more]

PMID: 37628976

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Project description:BackgroundCholangiocarcinoma is a highly heterogeneous tumor with bile acid metabolism involving in its development. The aim of this study was to characterize bile acid metabolism and identify specific subtypes to better stratify cholangiocarcinoma patients for individualized treatment and prognostic assessment.MethodsA total of 30 bile acids were quantified using the ultra-performance liquid chromatography tandem mass spectrometry. Using Consensus clustering, the molecular subtypes related to bile acid metabolism were identified. The prognosis, clinicopathologic characteristics, immune landscape, and therapeutic response were compared between these subtypes. The single-cell RNA sequencing (scRNA-seq) analysis and preliminary cell experiment were also conducted to verify our findings.ResultsThe altered bile acid profile and genetic variation of bile acid metabolism-related genes in cholangiocarcinoma were demonstrated. The cholangiocarcinoma was categorized into bile acid metabolism-active and -inactive subtypes with different prognoses, clinicopathologic characteristics, tumor microenvironments (TME) and therapeutic responses. This categorization was reproducible and predictable. Specifically, the bile acid metabolism-active subtype showed a poor prognosis with an immunosuppressive microenvironment and an inactive response to immunotherapy, while the bile acid metabolism-inactive subtype showed the opposite characteristics. Moreover, the scRNA-seq revealed that immunotherapy altered bile acid metabolism in TME of cholangiocarcinoma. Finally, a prognostic signature related to bile acid metabolism was developed, which exhibited strong power for prognostic assessment of cholangiocarcinoma. Consistently, these results were verified by immunohistochemistry, cell proliferation, migration, and apoptosis assays.ConclusionIn conclusion, a novel cholangiocarcinoma classification based on bile acid metabolism was established. This classification was significant for the estimation of TME and prognosis.

Dataset Information

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

Publications

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

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