Pathogenetic role of aberrant fucosylation in intrahepatic cholangiocarcinoma

Background Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignancy with limited therapeutic options. Aberrant protein glycosylation is a hallmark of cancer. Here, we investigated the levels of protein fucosylation and its role in iCCA development.

Methods Global protein fucosylation was determined using lectin histochemistry and Western blotting. The GDP-L-fucose synthetase (FX) and the GDP-fucose transmembrane transporter (SLC35C1), both major players of cellular fucosylation, were silenced via small interfering RNA. Moreover, iCCA cell lines were treated with 6-Alkynylfucose (6AF), a fucosylation inhibitor. In these cells, the fucosylation effects on the NOTCH and NF-kB pathways, two predominant cascades in cholangiocarcinogenesis and fucosylation targets, were also investigated.

Results Levels of global fucosylation and members of the fucosylation pathway were upregulated in human iCCA tissues compared to corresponding non-tumorous surrounding livers. Fucosylation inhibition following 6AF administration resulted in a dose-dependent decrease of proliferation and migration of iCCA cell lines. These effects were annulled by adding fucose to the cell medium. At the molecular level, 6AF administration or FX/SLC35C1 silencing led to the decrease of Notch receptors and related target genes in iCCA cell lines. In the same cells, NF-κB p65 and Bcl-xL protein levels diminished, whereas IκBα (a critical NF-kB inhibitor) increased after FX/SLC35C1 knockdown and drug addition.

Conclusions The present findings indicate that elevated global fucosylation characterizes iCCA. In this disease, fucosylation is involved in cell growth and migration and the upregulation of the NOTCH and NF-kB pathways. Thus, aberrant fucosylation is a novel pathogenetic player and a potential therapeutic target for human iCCA.

Publication History

Article published online:
26 January 2022