The cytokine-cosmc signaling axis upregulates the tumor-associated carbohydrate antigen Tn.

Chia-Wen Ho,Hung-Yun Lin,Jacqueline Whang-Peng,Jaulang Hwang,Yu-Tang Chin,Chiao-En Chen,Yi-Wei Liaw,Hsiao-Ling Chiang,Rui-Lan Huang,Earl Fu,Po-Jan Kuo,Chi-Yu Lin,Shin Nieh,Hung-Cheng Lai,Leroy F Liu,Yaw-Wen Hsu

doi:10.18632/oncotarget.11324

Chia-Wen Ho, Hung-Yun Lin + Show 14 more

Open Access

https://doi.org/10.18632/oncotarget.11324

Copy DOI

Abstract

Tn antigen (GalNAc-α-O-Ser/Thr), a mucin-type O-linked glycan, is a well-established cell surface marker for tumors and its elevated levels have been correlated with cancer progression and prognosis. There are also reports that Tn is elevated in inflammatory tissues. However, the molecular mechanism for its elevated levels in cancer and inflammation is unclear. In the current studies, we have explored the possibility that cytokines may be one of the common regulatory molecules for elevated Tn levels in both cancer and inflammation. We showed that the Tn level is elevated by the conditioned media of HrasG12V-transformed-BEAS-2B cells. Similarly, the conditioned media obtained from LPS-stimulated monocytes also elevated Tn levels in primary human gingival fibroblasts, suggesting the involvement of cytokines and/or other soluble factors. Indeed, purified inflammatory cytokines such as TNF-α and IL-6 up-regulated Tn levels in gingival fibroblasts. Furthermore, TNF-α was shown to down-regulate the COSMC gene as evidenced by reduced levels of the COSMC mRNA and protein, as well as hypermethylation of the CpG islands of the COSMC gene promoter. Since Cosmc, a chaperone for T-synthase, is known to negatively regulate Tn levels, our results suggest elevated Tn levels in cancer and inflammation may be commonly regulated by the cytokine-Cosmc signaling axis.

Highlights

Tn (GalNAc-α-O-Ser/Thr; N-acetyl-galactosamine alpha-O-linked to a serine or a threonine residue), a well-known mucin-type O-linked glycan, is abnormally overexpressed in a broad spectrum of cancers [1,2,3]
A significant increase in Tn levels were detected in both ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) of breast cancer tissues but not in normal breast tissues (Figure 1A)
Tn levels in human gingival fibroblasts (HGFs) replenished with one-day conditioned media from LPSstimulated U937 cells were observed to increase in an LPS-dose-dependent manner (Figure 4B)

Summary

Introduction

Tn (GalNAc-α-O-Ser/Thr; N-acetyl-galactosamine alpha-O-linked to a serine or a threonine residue), a well-known mucin-type O-linked glycan, is abnormally overexpressed in a broad spectrum of cancers [1,2,3]. Previous studies have shown that Tn antigen is an intermediate product in O-glycosylation of mucin and can be extended by the key enzyme T-synthase www.impactjournals.com/oncotarget (core 1 β-1, 3-galactosyltransferase or C1β3Gal-T) through transfer galactose from UDP-galactose (uridine diphosphate galactose) to generate T antigen [core 1; Galβ-(1→3)-GalNAc-α-O-Ser/Thr], found in several types of cancer [5]. The substrate specificity and specific molecular chaperon of T-synthase core 1 β3-Gal-T-specific molecular chaperone (Cosmc) have been demonstrated by previous studies [6,7,8]. Either a defective T-synthase or a decreased expression of Cosmc could prevent the extension of O-linked glycosylation of mucin, resulting in an apparently increased expression of Tn antigen. Tn antigen can be modified with sialic acid by α-2, 6-sialyltransferase (ST6GalNAc I) to produce sTn (sialyl Tn; Neu5Ac-α(2→6)-GalNAc-α-O-Ser/Thr), which is increased in cancer [9,10,11,12]

Methods

Results

Conclusion