Ament, Cindy E. and Steinmann, Sara and Evert, Katja and Pes, Giovanni M. and Ribback, Silvia and Gigante, Isabella and Pizzuto, Elena and Banales, Jesus M. and Rodrigues, Pedro M. and Olaizola, Paula and Wang, Haichuan and Giannelli, Gianluigi and Chen, Xin and Evert, Matthias and Calvisi, Diego F. (2023) Aberrant fucosylation sustains the NOTCH and EGFR/NF-κB pathways and has a prognostic value in human intrahepatic cholangiocarcinoma. HEPATOLOGY, 78 (6). pp. 1742-1754. ISSN 0270-9139, 1527-3350
Full text not available from this repository. (Request a copy)Abstract
Background and Aims:Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignancy, with increasing incidence worldwide and limited therapeutic options. Aberrant protein glycosylation is a hallmark of cancer. Here, we thoroughly investigated the possible involvement of fucosylation in cholangiocarcinogenesis.Approach and Results:We discovered that the levels of global fucosylation and members of the fucosylation pathway are ubiquitously upregulated in human iCCA tissues compared to nontumorous surrounding livers and normal biliary cells. In addition, total fucosylation levels correlate with poor patients' prognosis. Furthermore, fucosylation inhibition following 6-alkynylfucose (6AF) administration triggered a dose-dependent decrease in the proliferation and migration of iCCA cell lines. Notably, adding fucose to the cell medium annulled these effects. At the molecular level, 6AF administration or small interfering RNA-mediated silencing of GDP-L-fucose synthetase (FX) and the GDP-fucose transmembrane transporter (SLC35C1), both pivotal players of cellular fucosylation, decreased NOTCH activity, NOTCH1/Jagged1 interaction, NOTCH receptors, and related target genes in iCCA cell lines. In the same cells, EGFR, nuclear factor kappa-light-chain-enhancer of activated B cells p65, and Bcl-xL protein levels diminished, whereas I & kappa;B & alpha; (a critical cellular NF-& kappa;B inhibitor) increased after FX/SLC35C1 knockdown or 6AF administration. In the chick chorioallantoic membrane assay, 6AF treatment profoundly suppresses the growth of iCCA cells.Conclusions:Elevated global fucosylation characterizes human iCCA, contributing to cell growth and migration through the upregulation of the NOTCH and EGFR/NF-& kappa;B pathways. Thus, aberrant fucosylation is a novel pathogenetic player and a potential therapeutic target for human iCCA.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NF-KAPPA-B; DIAGNOSIS; GROWTH |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 May 2024 08:47 |
| Last Modified: | 14 May 2024 08:47 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60217 |
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