Faculty, Staff and Student Publications
Publication Date
1-1-2025
Journal
Liver International
Abstract
BACKGROUND & AIMS: GD2, a member of the ganglioside (GS) family (sialic acid-containing glycosphingolipids), is a potential biomarker of cancer stem cells (CSC) in several tumours. However, the possible role of GD2 and its biosynthetic enzyme, GD3 synthase (GD3S), in intrahepatic cholangiocarcinoma (iCCA) has not been explored.
METHODS: The stem-like subset of two iCCA cell lines was enriched by sphere culture (SPH) and compared to monolayer parental cells (MON). GS profiles were evaluated by chromatography, after feeding with radioactive sphingosine. Membrane GD2 expression was evaluated by FACS, and the expression of enzymes of GS biosynthesis was analysed by RT-qPCR. The modulation of stem features by GS was investigated in vitro and in vivo using GD3S-overexpressing cells and corroborated by global transcriptomic analysis.
RESULTS: GS composition was markedly different comparing SPH and MON. Among complex GS, iCCA-SPH showed increased GD2 levels, in agreement with the high expression levels of GD3 and GM2/GD2 synthases. iCCA cells overexpressing GD3S had higher sphere-forming ability, invasive properties and drug resistance than parental cells. NOD/SCID mice implanted with CCLP1 cells overexpressing GD3S developed larger tumours than control cells. By global transcriptomic analysis, ontology investigation identified 74 processes shared by the iCCA-SPH and GD3S-transfected cells, with enrichment for development and morphogenesis processes, MAPK signalling and locomotion. In a cohort of patients with iCCA, GD3S expression was correlated with lymph node invasion, indicating a possible relevance of GD3S in the clinical setting.
CONCLUSIONS: The profile of GS derivatives regulates the stem-like properties of iCCA cells.
Keywords
Cholangiocarcinoma, Gangliosides, Humans, Bile Duct Neoplasms, Neoplastic Stem Cells, Cell Line, Tumor, Sialyltransferases, Animals, Phenotype, Mice, Mice, SCID, cancer stem cells, cancer stemness biomarker, GD2 ganglioside, GD3 synthase (o ST8SIA1), intrahepatic cholangiocarcinoma
DOI
10.1111/liv.16208
PMID
39726234
PMCID
PMC11684508
PubMedCentral® Posted Date
12-26-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Sciences Commons, Oncology Commons
