Many tumor-associated antigens are carbohydrates found in cell surface and secreted mucins, such as the truncated Tn (GalNAca-Ser/Thr) or sialyl-Tn antigens (NeuAca6-GalNAca-Ser/Thr) in O-glycans, and in glycoprotein N-glycans, and glycolipids, such as the Lewis antigens. The Tn antigen in particular is found in >90% of human carcinomas. In normal tissues these antigens are either missing or masked, since in normal cells the Tn antigen is modified to generate the T antigen (Gal(33-GalNAca-Ser/Thr), and its derivatives such as sialyl T, and disialyl T antigens. We recently identified a novel X-linked gene Cosmc, which has a single exon encoding a molecular chaperone Cosmc that regulates mucin glycosylation through regulating the formation of active core 1 |33-galactosyltransferase (T-synthase). Preliminary results show that point mutations in Cosmc in human tumor cell lines leads to loss of T-synthase activity and expression of Tn and sialyl-Tn antigens. Cosmc is the first example of a genetic mutation in tumor cells causing specific alterations in mucin glycosylation. Thus, we hypothesize that somatic cell mutations in Cosmc lead to altered mucin glycosylation and expression of tumor-associated antigens. These antigens may result in altered tumor cell adhesion and promote tumor cell growth, survival, and metastasis. To explore this hypothesis, we will define whether there is a correlation in human cervican cancer specimens between expression of the Tn/sialyl-Tn antigens and Cosmc mutations. We will also examine expression of other glycan-based antigens not restricted to mucins, e.g., the Lewis antigens (sialyl Lewis a and sialyl Lewis x). Cells within immunostained sections expressing the Tn and sialyl Tn antigens will be laser microdissected and the DNA and cDNA sequences of Cosmc and control genes, such as T-synthase, will be examined. These studies should provide novel information about the factors regulating mucin glycosylation and expression of tumor-associated antigens. ? ?
| Ju, Tongzhong; Lanneau, Grainger S; Gautam, Tripti et al. (2008) Human tumor antigens Tn and sialyl Tn arise from mutations in Cosmc. Cancer Res 68:1636-46 |
