Background and objectives: Sialylation plays important roles in tumor progression. Our present study aimed to demonstrate the alteration of sialylation and its role in cholangiocarcinoma (CCA). Materials and Methods: The α2,3- and α2,6-sialylation in CCA tissue was analyzed by lectin-histochemistry using Maackia amurensis lectin-II (MAL-II) and Sambucus nigra agglutinin (SNA). CCA cell lines were treated with the pan-sialylation inhibitor 3Fax-peracetyl-Neu5Ac (3F-Sia) followed by proliferation and chemosensitivity assays. Results: MAL-II binding α2,3-Sialylated Glycan (MAL-SG) and SNA binding α2,6-Sialylated Glycan (SNA-SG) were both elevated in CCA compared with hyperplastic/dysplastic (HP/DP) and normal bile ducts (NBD). The positive staining for MAL-SG or SNA-SG were found in 82% (61/74) of the CCA cases. Higher expression of MAL-SG in CCA was associated with shorter survival of the patients. The median survival of patients with high and low MAL-SG were 167 and 308 days, respectively, with overall survival of 233 days, suggesting the involvement of MAL-SG in CCA progression. MAL-SG expression of CCA cell lines was markedly decreased after treatment with 3F-Sia for 48 to 72 h. While proliferation of CCA cells were not affected by 3F-Sia treatment, their susceptibility to 5-fluorouracil (5-FU) was significantly enhanced. These results suggest that sialylation is involved in the development of 5-FU resistance and the sialylation inhibitor 3F-Sia can be used as a chemosensitizer for CCA. Conclusions: Sialylation is critically involved in the development of chemoresistance of CCA, and sialylation inhibitors may be used as a chemosensitizer in CCA treatment.

Cholangiocarcinoma (CCA) is a highly metastatic tumor, and the majority of patients with CCA have a short survival time because there are no available effective treatments. Hence, a better understanding regarding CCA metastasis may provide an opportunity to improve the strategies for treatment. A comparison study between the highly metastatic cells and their parental cells is an approach to uncover the molecular mechanisms underlying the metastatic process. In the present study, a lung metastatic CCA cell line, KKU-214L5, was established by the in vivo selection of the tail vein-injected mouse model. KKU-214L5 cells possessed mesenchymal spindle-like morphology with higher migration and invasion abilities in vitro than the parental cells (KKU-214). KKU-214L5 also exhibited extremely aggressive lung colonization in the tail vein-injected metastatic model. Epithelial-mesenchymal transition (EMT) was clearly observed in KKU-214L5 cells. Significant downregulation of epithelial markers (ZO-1 and claudin-1), with unique upregulation of E-cadherin and mesenchymal markers (vimentin, β-catenin, and slug), was observed in KKU-214L5. Increasing MMP-2 and MMP-9 activities and CD147 expression reflected the high invasion activity in KKU-214L5 cells. Suppression of vimentin using siRNA significantly decreased the migration and invasion capabilities of KKU-214L5 to almost the basal levels of the parental cells without any change on the expression levels of other EMT markers and the activities of MMPs. These results suggest that vimentin activation is essential to potentiate the metastatic characters of CCA cells, and suppression of vimentin expression could be a potential strategy to improve the treatment of CCA, a highly metastatic cancer.

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Background and objectives: Cancer-associated carbohydrate antigen 50 (CA50) is a marker for detection of gastrointestinal cancers, especially of pancreatic and colon cancer. In this study, the power of CA50 as a diagnostic and prognostic marker was evaluated in intrahepatic cholangiocarcinoma (iCCA). Materials and Methods: Serum CA50 levels of iCCA patients and non-cholangiocarcinoma controls (non-CCA, including healthy persons and patients with benign biliary diseases and other gastrointestinal cancers) were measured using MAGLUMI®800 CLIA analyzer. Diagnostic and prognostic values of serum CA50 levels were evaluated. Results: CA50 levels in the sera of iCCA patients were significantly higher than those of non-CCA controls (p < 0.001, Mann–Whitney U test). Using cut-off value of 25 U/mL, CA50 provided 65.9% sensitivity, 87.3% specificity, and 80.1% accuracy for diagnosis of iCCA. Serum CA50 levels were increased and associated with the severity of bile duct pathology. In addition, a higher level of CA50 was associated with poor clinical outcome and shorter survival in iCCA patients. Multivariate survival analysis by Cox regression model revealed the potential of CA50 as an independent poor prognostic indicator for iCCA, regardless of the age, sex, histological types, or tumor stages. Conclusions: CA50 can be a diagnostic and poor prognostic marker candidate for iCCA.