Published online Jun 21, 2019. doi: 10.3748/wjg.v25.i23.2947
Peer-review started: March 14, 2019
First decision: April 11, 2019
Revised: April 25, 2019
Accepted: May 18, 2019
Article in press: May 18, 2019
Published online: June 21, 2019
Changes in N-linked glycosylation have been observed in the circulation of individuals with hepatocellular carcinoma. In particular, an elevation in the level of core fucosylation has been observed. However, the mechanisms through which core fucose is increased are not well understood. We hypothesized that a review of the literature and related bioinformatic review regarding six genes known to be involved in the attachment of core fucosylation, the synthesis of the fucosylation substrate guanosine diphosphate (GDP)-fucose, or the transport of the substrate into the Golgi might offer mechanistic insight into the regulation of core fucose levels.
To survey the literature to capture the involvement of genes regulating core N-linked fucosylation in hepatocellular carcinoma
The PubMed biomedical literature database was searched for the association of hepatocellular carcinoma and each of the core fucose-related genes and their protein products. We also queried The Cancer Genome Atlas Liver hepatocellular carcinoma (LIHC) dataset for genetic, epigenetic and gene expression changes for the set of six genes using the tools at cBioportal.
A total of 27 citations involving one or more of the core fucosylation-related genes (FPGT, FUK, FUT8, GMDS, SLC35C1, TSTA3) and hepatocellular carcinoma were identified. The same set of gene symbols was used to query the 371 patients with liver cancer in the LIHC dataset to identify the frequency of mRNA over or under expression, as well as non-synonymous mutations, copy number variation and methylation level. Although all six genes trended to more samples displaying over expression relative to under-expression, it was noted that a number of tumor samples had undergone amplification of the genes of the de novo synthesis pathway, GMDS (27 samples) and TSTA3 (78 samples). In contrast, the other four genes had undergone amplification in 2 or fewer samples.
Amplification of genes involved in the de novo pathway for generation of GDP-fucose, GMDS and TSTA3, likely contributes to the elevated core fucose observed in hepatocellular carcinoma.
Core tip: The increased level of core fucosylated N-linked glycoproteins detected in some patients with hepatocellular carcinoma may occur via several potential molecular mechanisms. We report that the genes GMDS and TSTA3, which are associated with the de novo synthesis of the fucose donor species, guanosine diphosphate fucose, can be amplified in some hepatocellular carcinoma patients. Amplification seems to be the most common genetic alteration affecting the genes that control the production of core fucosylated proteins.