Ganglioside GM3 participates in the TGF-β1-induced epithelial–mesenchymal transition of human lens epithelial cells

Abstract

TGF-β (transforming growth factor-β)-induced EMT (epithelial-mesenchymal transition) induces the proliferation and migration of the HLE (human lens epithelial) cells. Ganglioside GM3, simple sialic-acid-containing glycosphingolipids on mammalian cell membranes, regulates various pathological phenomena such as insulin resistance and tumour progression. However, the relationship between ganglioside GM3 and TGF-β-induced EMT in the HLE B-3 cells is poorly understood. In the present study we demonstrated that ganglioside GM3 was involved in TGF-β1-induced EMT in HLE B-3 cells. Our results indicated that the expression of ganglioside GM3 and GM3 synthase mRNA were significantly increased in TGF-β1-induced HLE B-3 cells. Reporter gene analysis also demonstrated that transcriptional activation of the GM3 synthase gene was regulated by Sp1 (specificity protein 1) in HLE B-3 cells upon TGF-β1 stimulation. Interestingly, the inhibition of ganglioside GM3 expression by d-PDMP [d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol] and GM3 synthase shRNA (short hairpin RNA) resulted significantly in the suppression of cell migration and EMT-related signalling in HLE B-3 cells stimulated by TGF-β. Furthermore, exogenous treatment of ganglioside GM3 rescued the expression of EMT molecules and cell migration suppressed by the depletion of ganglioside GM3 in TGF-β1-induced HLE B-3 cells. We also found that ganglioside GM3 interacted with TGFβRs (TGF-β receptors) in TGF-β1-induced HLE B-3 cells. Taken together, these results suggest that ganglioside GM3 induced by TGF-β1 regulates EMT by potential interaction with TGFβRs.

miRNA proxy approach reveals hidden functions of glycosylation

“…Glycogenes inhibited when miR-200f levels are high ( Left , green arrow, red glycogenes) and promoted by loss of miR-200f ( Right , red arrow, green glycogenes) alter glycosylation in multiple contexts including receptor signaling (36), protein secretion (40), and cell-adhesion networks (29–31). …”

“…MiR-200f is a regulatory component of the TGF-β EMT-signaling pathway, implying that B3GLCT, ST6GALNAC5 , and ST3GAL5 also are components of that pathway. Increased levels of the glycolipid GM3, the product of ST3GAL5 , have been shown to promote the dimerization and activation of TGF-β receptors (36). However, B3GLCT and ST6GALNAC5 are not known to be involved in EMT.…”

EMT Factors and Metabolic Pathways in Cancer

“…Last, the metabolism of complex lipids and specifically glycosphingolipids has been shown to affect EMT. GM3 synthase converts lactosyl ceramide to a simple ganglioside called GM3 which is known to promote EMT by interacting with TGFβ receptors (275). It has been shown that ZEB1 can induce GM3 synthase gene by binding to its promoter and by repressing the micro-RNA mediated suppression of GM3 synthase in human lung cancer cells (122).…”

Altered (neo-) lacto series glycolipid biosynthesis impairs α2-6 sialylation on N-glycoproteins in ovarian cancer cells

“…They also interact with well-known proteins such as EGFR2, TGFβ1R3, and VEGFR4 in various malignancies. GSLs are usually divided into two major families, known as galactosylated or glucosylated ceramides.…”