Abstract
BackgroundLigands of the C-type lectin CLEC10A such as Tn and sialyl-Tn representing early intermediates of O-glycosylation are hallmarks of many human malignancies. A variety of regulatory mechanisms underlying their expression are being discussed.MethodsCLEC10A ligands were detected in various tissues and cells using the recombinant glycan-binding domain of CLEC10A. In normal breast and endometrium, presence of ligands was correlated to the female cycle. Estrogen- and stress dependent induction of CLEC10A ligands was analyzed in MCF7 and T47D cells exposed to 4-hydroxy-tamoxifen (Tam), zeocin and hydrogen peroxide. The expression and localization of CLEC10A ligands was analyzed by Western blot and immunofluorescence. In breast cancer patients CLEC10A ligand expression and survival was correlated by Kaplan-Meyer analysis.ResultWe observed binding of CLEC10A in normal endometrial and breast tissues during the late phase of the female hormonal cycle suggesting a suppressive effect of female sex hormones on CLEC10A ligand expression. Accordingly, CLEC10A ligands were induced in MCF7- and T47D breast cancer cells after Tam treatment and accumulated on the cell surface and in the endosomal/lysosomal compartment. Phagocytosis experiments indicate that macrophages preferentially internalize CLEC10A ligands coated beads and Tam treated MCF7 cells. CLEC10A ligands were also expressed after the addition of zeocin and hydrogen-peroxide. Each substance induced the production of ROS indicating reactive oxygen species as a unifying mechanism of CLEC10A ligand induction. Mechanistically, increased expression of GalNAc-transferase 6 (GalNT6) and translocation of GalNT2 and GalNT6 from cis- towards trans-Golgi compartment was observed, while protein levels of COSMC and T-synthase remained unaffected. In breast cancer patients, positivity for CLEC10A staining in tumor tissues was associated with improved outcome and survival.ConclusionCLEC10A ligands are inducible by hormone depletion, 4-hydroxy-tamoxifen and agents inducing DNA damage and oxidative stress. Our results indicate that CLEC10A acts as a receptor for damaged and dead cells and may play an important role in the uptake of cell debris by macrophages and dendritic cells.Graphical
Highlights
Ligands of the C-type lectin CLEC10A such as Tn and sialyl-Tn representing early intermediates of Oglycosylation are hallmarks of many human malignancies
Hormone-dependent expression of CLEC10A positive glycan structures in normal human tissues Based on protein domain histochemistry, we previously investigated the binding of the glycoreceptor CLEC10A to breast cancer tissue
We demonstrate that estrogen depletion and treatment of breast cancer cell lines by Tam, zeocin and hydrogen peroxide lead to the enhanced presentation of CLEC10A ligands
Summary
Ligands of the C-type lectin CLEC10A such as Tn and sialyl-Tn representing early intermediates of Oglycosylation are hallmarks of many human malignancies. Up to 80% of breast cancers express the estrogen receptor (ER) [2]. The Tn-structure represents the initial step of O-glycan synthesis involving at least 20 different GalNAc-transferases (GalNTs) and may serve as an acceptor for the sialyltransferase ST6GalNAc-I, yielding sialyl-Tn (STn). Since COSMC- and T-synthase mutations are a rare event in breast cancer, other mechanisms likely contribute to the increased expression of truncated O-glycans. One potential mechanism involve a shift in the localization of glycosyltransferases in organelle compartments after stimulation with growth factors like EGF or PDGF leading to altered glycosylation [11, 12]. Elevated pH in the Golgi apparatus appears to be linked to T-antigen expression in cancer cells by affecting the distribution of Golgi-localized glycosyltransferases [13]
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