Serum N-glycome biomarker for monitoring development of DENA-induced hepatocellular carcinoma in rat

Abstract

BackgroundThere is a demand for serum markers for the routine assessment of the progression of liver cancer. We previously found that serum N-linked sugar chains are altered in hepatocellular carcinoma (HCC). Here, we studied glycomic alterations during development of HCC in a rat model.ResultsRat HCC was induced by the hepatocarcinogen, diethylnitrosamine (DENA). N-glycans were profiled using the DSA-FACE technique developed in our laboratory.In comparison with control rats, DENA rats showed a gradual but significant increase in two glycans (R5a and R5b) in serum total N-glycans during progression of liver cirrhosis and cancer, and a decrease in a biantennary glycan (P5). The log of the ratio of R5a to P1 (NGA2F) and R5b to P1 [log(R5a/P1) and log(R5b/P1)] were significantly (p < 0.0001) elevated in HCC rats, but not in rats with cirrhosis or fibrosis or in control rats. We thus propose a GlycoTest model using the above-mentioned serum glycan markers to monitor the progression of cirrhosis and HCC in the DENA-treated rat model. When DENA-treated rats were subsequently treated with farnesylthiosalicyclic acid, an anticancer drug, progression to HCC was prevented and GlycoTest markers (P5, R5a and R5b) reverted towards non-DENA levels, and the HCC-specific markers, log(R5a/P1) and log(R5b/P1), normalized completely. Conclusions: We found an increase in core-α-1,6-fucosylated glycoproteins in serum and liver of rats with HCC, which demonstrates that fucosylation is altered during progression of HCC. Our GlycoTest model can be used to monitor progression of HCC and to follow up treatment of liver tumors in the DENA rat. This GlycoTest model is particularly important because a rapid non-invasive diagnostic procedure for tumour progression in this rat model would greatly facilitate the search for anticancer drugs.

Extracellular Matrix Remodeling: The Common Denominator in Connective Tissue DiseasesPossibilities for Evaluation and Current Understanding of the Matrix as More Than a Passive Architecture, but a Key Player in Tissue Failure

“…Promising candidates have been reported, including those derived from type IV collagen, 196,197 type I collagen, 198 type V collagen, 199 and type VI collagen. 200 Systemic approaches, such as global profiling of serum glycoproteins, have also been utilized, 201 and this technique is now being validated in rodent models (e.g., Fang et al, 202 Blomme et al,…”

Protein and Site Specificity of Fucosylation in Liver-Secreted Glycoproteins

“… 5 − 7 One of the best documented examples of aberrant glycosylation is the progression of liver disease to hepatocellular carcinoma (HCC). 8 , 9 In the case of liver disease, changes in protein N-glycosylation can be analyzed efficiently by serologic monitoring of liver-secreted glycoproteins. 10 − 12 Reported changes of N-glycan repertoire in cancer include the formation of bisecting glycans with one molecule of N -acetylglucosamine attached via β1–4 bond to the branched core mannose, asialo and agalacto glycans, truncated structures with terminal galactoses or N -acetylglucosamines, (poly)- N -acetyllactosamines with beta 1–6 branching, and fucosylated glycans with fucose attached mainly at the C-3 position of outer arm N -acetylglucosamine or less frequently at the C-6 N -acetylglucosamine of the N-glycan core.…”

Aberrant fucosylation of glycosphingolipids in human hepatocellular carcinoma tissues

“…Glycoconjugates are important information-bearing biomacromolecules of the cell membrane, and abnormal expression levels of glycoconjugates in tumours have been reported (7). Previous studies with HCC patients have focused on the abnormal expression of glycoproteins (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Souady et al recently reported that CD75s-and iso-CD75s-ganglioside expression in HCC cells is associated with poor histopathological differentiation (19).…”