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Discovery of Serotransferrin Glycoforms: Novel Markers for Diagnosis of Liver Periductal Fibrosis and Prediction of Cholangiocarcinoma.

ABSTRACT: Cholangiocarcinoma (CCA) caused by chronic liver fluke infection is a major public health problem in Northeast Thailand. Identification of CCA risk groups is urgently needed for the control of CCA in this region. Periductal fibrosis (PDF) induced by chronic inflammation of bile ducts is known as a pre-neoplastic lesion of CCA. We aimed to identify the serum CCA and PDF biomarkers using mass spectrometry (UPLC-ESI-QqQ) with multiple reaction mode (MRM) analysis. Here, serum levels of serotransferrin glycoforms at the glycopeptide level were measured in the sera of CCA (n = 100), PDF (n = 50), and healthy control (n = 100) subjects. The results indicated that serotransferrin peptide levels were generally the same between the control and PDF groups, whereas CCA patients had reduced levels. Moreover, 56 serotransferrin glycoforms were detected, with nine increased in CCA compared to control subjects. Among them, the serum levels of four glycoforms were increased in PDF and CCA patients compared to control subjects. In particular, highly sialylated multi-branched glycans of serotransferrin serum were significantly correlated with poor prognosis and tumor stage in CCA patients. Taken together, these glycoforms could be used as risk biomarkers and prognosis and diagnosis markers of CCA.

SUBMITTER: Jamnongkan W

PROVIDER: S-EPMC6843847 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Discovery of Serotransferrin Glycoforms: Novel Markers for Diagnosis of Liver Periductal Fibrosis and Prediction of Cholangiocarcinoma.

Jamnongkan Wassana W Lebrilla Carlito B CB Barboza Mariana M Techasen Anchalee A Loilome Watcharin W Sithithaworn Paiboon P Khuntikeo Narong N Pairojkul Chawalit C Chamadol Nittaya N Thanan Raynoo R Yongvanit Puangrat P

Biomolecules 20190927 10

Cholangiocarcinoma (CCA) caused by chronic liver fluke infection is a major public health problem in Northeast Thailand. Identification of CCA risk groups is urgently needed for the control of CCA in this region. Periductal fibrosis (PDF) induced by chronic inflammation of bile ducts is known as a pre-neoplastic lesion of CCA. We aimed to identify the serum CCA and PDF biomarkers using mass spectrometry (UPLC-ESI-QqQ) with multiple reaction mode (MRM) analysis. Here, serum levels of serotransfer ...[more]

PMID: 31569686

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Project description:BackgroundLiver fibrosis is a consequence of chronic inflammation and is associated with protein changes within the hepatocytes structure. In this study, we aimed to investigate if this is reflected by the urinary proteome and can be explored to diagnose liver fibrosis in patients with chronic liver disease.MethodsIn a multicentre combined cross-sectional and prospective diagnostic test validation study, 129 patients with varying degrees of liver fibrosis and 223 controls without liver fibrosis were recruited. Additionally, 41 patients with no liver, but kidney fibrosis were included to evaluate interference with expressions of kidney fibrosis. Urinary low molecular weight proteome was analysed by capillary electrophoresis coupled to mass spectrometry (CE-MS) and a support vector machine marker model was established by integration of peptide markers for liver fibrosis.FindingsCE-MS enabled identification of 50 urinary peptides associated with liver fibrosis. When combined into a classifier, LivFib-50, it separated patients with liver fibrosis (N = 31) from non-liver disease controls (N = 123) in cross-sectional diagnostic phase II evaluation with an area under the curve (AUC) of 0.94 (95% confidence intervals (CI): 0.89-0.97, p<0.0001). When adjusted for age, LivFib-50 demonstrated an AUC of 0.94 (95% CI: 0.89-0.97, p<0.0001) in chronic liver disease patients with (N = 19) or without (N = 17) liver fibrosis progression. In this prospective diagnostic phase III validation set, age-adjusted LivFib-50 showed 84.2% sensitivity (95% CI: 60.4-96.6) and 82.4% specificity (95% CI: 56.6-96.2) for detection of liver fibrosis. The sequence-identified peptides are mainly fragments of collagen chains, uromodulin and Na/K-transporting ATPase subunit γ. We also identified ten putative proteolytic cleavage sites, eight were specific for matrix metallopeptidases and two for cathepsins.InterpretationIn liver fibrosis, urinary peptides profiling offers potential diagnostic markers and leads to discovery of proteolytic sites that could be targets for developing anti-fibrotic therapy.

Dataset Information

Discovery of Serotransferrin Glycoforms: Novel Markers for Diagnosis of Liver Periductal Fibrosis and Prediction of Cholangiocarcinoma.

Publications

Discovery of Serotransferrin Glycoforms: Novel Markers for Diagnosis of Liver Periductal Fibrosis and Prediction of Cholangiocarcinoma.

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