The membrane-bound mucins: how large O-glycoproteins play key roles in epithelial cancers and hold promise as biological tools for gene-based and immunotherapies

Abstract

Membrane-bound mucins belong to an ever-increasing family of O-glycoproteins that share a structure conserved throughout evolution. Typically, membrane-bound mucins contain a long extracellular domain, a hydrophobic transmembrane domain, and a short cytoplasmic tail. They are modular proteins and have a structural organization containing Pro/ Thr/Ser-rich O-glycosylated domains and EGF-like domains. The biological roles of mucins arise from their structures. MUC1 and MUC4 modulate biological properties of the cell, alter its behavior and modulate cell signaling pathways associated with tumorigenesis. Altered expression and post-translational modifications confer an important role to MUC1 and MUC4 in tumor progression, metastasis, and cancer cell chimioresistance. Moreover, increasing knowledge about their animal counterparts has made possible a greater understanding of their pathophysiological role in vivo. Most biological functions attributed to MUC4 are based on the structural homology with its rat homologue. From these results, the development of new biological tools targeting mucins has been increasing and the recent attention given to these complex molecules may bring hope for improved cancer treatments in the future. This review discusses the structure/function of MUC1 and MUC4 membrane-bound mucins in relation to cancer cell behavior and cell signaling pathways associated with tumorigenesis, as well as their potential as biological tools for gene therapy and immunotherapy approaches.