Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis

Abstract

Mucins are large O-glycoproteins with high carbohydrate content and marked diversity in both the apoprotein and the oligosaccharide moieties. All three mucin types, trans-membrane (e.g., MUC1, MUC4, MUC16), secreted (gel-forming) (e.g., MUC2, MUC5AC, MUC6) and soluble (non-gel-forming) (e.g., MUC7, MUC8, MUC9, MUC20), are critical in maintaining cellular functions, particularly those of epithelial surfaces. Their aberrant expression and/or altered subcellular localization is a factor of tumour growth and apoptosis induced by oxidative stress and several anti-cancer agents. Abnormal expression of mucins was observed in human carcinomas that arise in various gastrointestinal organs. It was widely believed that hepatocellular carcinoma (HCC) does not produce mucins, whereas cholangiocarcinoma (CC) or combined HCC-CC may produce these glycoproteins. However, a growing number of reports shows that mucins can be produced by HCC cells that do not exhibit or are yet to undergo, morphological differentiation to biliary phenotypes. Evaluation of mucin expression levels in precursors and early lesions of CC, as well as other types of primary liver cancer (PLC), conducted in in vitro and in vivo models, allowed to discover the mechanisms of their action, as well as their participation in the most important signalling pathways of liver cystogenesis and carcinogenesis. Analysis of mucin expression in PLC has both basic research and clinical value. Mucins may act as oncogenes and tumour-promoting (e.g., MUC1, MUC13), and/or tumour-suppressing factors (e.g., MUC15). Given their role in promoting PLC progression, both classic (MUC1, MUC2, MUC4, MUC5AC, MUC6) and currently tested mucins (e.g., MUC13, MUC15, MUC16) have been proposed to be important diagnostic and prognostic markers. The purpose of this review was to summarize and update the role of classic and currently tested mucins in pathogenesis of PLC, with explaining the mechanisms of their action in HCC carcinogenesis. It also focuses on determination of the diagnostic and prognostic role of these glycoproteins in PLC, especially focusing on HCC, CC and other hepatic tumours with- and without biliary differentiation.