Multiple roles of mucins in pancreatic cancer, a lethal and challenging malignancy

Abstract

Mucins are members of an expanding family of large multifunctional glycoproteins. Pancreatic mucins have important biological functions, including the protection, lubrication, and moisturisation of the surfaces of epithelial tissues lining ductal structures within the pancreas. Several lines of evidence support the notion that deregulated mucin production is a hallmark of inflammatory and neoplastic disorders of the pancreas. Herein, we discuss the factors that contribute to the lethality of pancreatic cancer as well as the key role played by mucins, particularly MUC1 and MUC4, in the development and progression of the disease. Aspects pertaining to the aberrant expression and glycosylation of mucins are discussed, with special emphasis on their potential impact on the design and implementation of adequate diagnostic and therapeutic strategies for combating this lethal malignancy.

Figure 1

(A) Schematic representation of the deduced amino-acid sequence of the MUC1, MUC2, and MUC4 genes, which are deregulated in PC. The MUC1 apomucin has an apparent simple structure with a central domain composed of sequences repeated in tandem, a transmembrane sequence, and a cytoplasmic tail. MUC4 is a heterodimeric protein, composed of an 850-kDa mucin-type α subunit, noncovalently linked to an 80-kDa growth-factor-like membrane-bound β subunit. MUC2 is a secreted mucin with several domains similar to the von Willebrand factor. Keys to figure: black, signal peptide; vertical lines, tandem repeat; diagonal lines serine, threonine-rich nonrepetitive sequence domain; dense dots, domain rich in N-glycosylation sites; open box, unique sequence; hatched boxes, cystein-rich domain; hatched ovals, EGF-like domain; light grey, transmembrane domain; small dots, cytoplasmic tail; descending hatched lines, D domains; ascending hatched lines, CK domain; horizontal lines, C domain; dense vertical lines, B domain. (B) Schematic representation of the PanIN lesions and MUC1, 2, and 4 expression during the progression of PC. Pancreatic intraepithelial neoplasias are thought to mimic the development of PC, evolving from PanIN-1A (flat epithelial lesions composed of tall columnar cells with basally located nuclei) to PanIN-3 (papillary lesion with budding off of small clusters of epithelial cells into the lumen). (C) Expression of MUC1, MUC2, and MUC4 in IPMT.