Differential expression of ST6GALNAC1 and ST6GALNAC2 and their clinical relevance to colorectal cancer progression

Abstract

Colorectal cancer (CRC) has become a significant global health concern and ranks among the leading causes of morbidity and mortality worldwide. Due to its malignant nature, current immunotherapeutic treatments are used to tackle this issue. However, not all patients respond positively to treatment, thereby limiting clinical effectiveness and requiring the identification of novel therapeutic targets to optimise current strategies. The putative ligand of Siglec-15, Sialyl-Tn (STn), is associated with tumour progression and is synthesised by the sialyltransferases ST6GALNAC1 and ST6GALNAC2. However, the deregulation of both sialyltransferases within the literature remain limited, and the involvement of microRNAs (miRNAs) in STn production require further elucidation. Here, we identified miRNAs involved in the regulation of ST6GALNAC1 via a computational approach and further analysis of miRNA binding sites were determined. In silico tools predicted miR-21, miR-30e and miR-26b to regulate the ST6GALNAC1 gene, all of which had shown significant upregulated expression in the tumour cohort. Moreover, each miRNA displayed a high binding affinity towards the seed region of ST6GALNAC1. Additionally, enrichment analysis outlined pathways associated with several cancer hallmarks, including epithelial to mesenchymal transition (EMT) and MYC targets associated with tumour progression. Furthermore, our in silico findings demonstrated that the ST6GALNAC1 expression profile was significantly downregulated in CRC tumours, and its low expression correlated with poor survival outcomes when compared with patient survival data. In comparison to its counterpart, there were no significant differences in the expression of ST6GALNAC2 between normal and malignant tissues, which was further evidenced in our immunohistochemistry analysis. Immunohistochemistry staining highlighted significantly higher expression was more prevalent in normal human tissues with regard to ST6GALNAC1. In conclusion, the integrated in silico analysis highlighted that STn production is not reliant on deregulated sialyltransferase expression in CRC, and ST6GALNAC1 expression is regulated by several oncomirs. We proposed the involvement of other sialyltransferases in the production of the STn antigen and CRC progression via the Siglec-15/Sia axis.