Liver membrane proteome glycosylation changes in mice bearing an extra-hepatic tumour

Published online first on February 18, 2010. Cancer is well known to be associated with alterations in membrane protein glycosylation(1-3). Equally, it has been well established that tumour-associated inflammation through the release of pro-inflammatory cytokines is a common cause of reduced hepatic drug metabolism and increased toxicity in advanced cancer patients being treated with cytotoxic chemotherapies. However, little is known about the impact of bearing a tumour (and downstream effects like inflammation) on liver membrane protein glycosylation. In this study, proteomic and glycomic analyses were used in combination to determine whether liver membrane protein glycosylation was affected in mice bearing the Engelbreth-Holm Swarm (EHS) sarcoma. Peptide IPG-IEF and label-free quantitation determined that many enzymes involved in the protein glycosylation pathway specifically; mannosidases (Man1a-I, Man1b-I and Man2a-I), mannoside N-acetylglucosaminyltransferases (Mgat-I and Mgat-II), galactosyltransferases (B3GalT-VII, B4GalT-I, B4GalT-III, C1GalT-I, C1GalT-II and GalNT-I) and sialyltransferases (ST3Gal-I, ST6Gal-I and ST6GalNAc-VI) were upregulated in all livers of tumour-bearing mice (n=3) compared to non-tumour bearing controls (n=3). In addition, many cell surface lectins: Sialoadhesin-1 (Siglec-1), C-type lectin family 4f (Kupffer cell receptor) and Galactose-binding lectin 9 (Galectin-9) were determined to be upregulated in the liver of tumour-bearing compared to control mice. Global glycan analysis identified seven N-glycans and two O-glycans that had changed on the liver membrane proteins derived from tumour-bearing mice.. Interestingly, a(2,3) sialic acid was found to be upregulated on the liver membrane of tumour-bearing mice which reflected the increased expression of its associated sialyltransferase and lectin receptor (siglec-1). The overall increased sialylation on the liver membrane of EHS bearing mice correlates with the increased expression of their associated glycosyltransferases and suggests that glycosylation of proteins in the liver plays a role in tumour-induced liver inflammation.58 page(s