Transmembrane mucins in lung adenocarcinoma: understanding of current molecular mechanisms and clinical applications

Abstract

The mucin family is a group of highly glycosylated macromolecules widely present in human epithelial cells and with subtypes of secreted and membrane-associated forms. The membrane-associated mucins, known as transmembrane mucins, are not only involved in the formation of mucus barrier but also regulate cell signal transduction in physiological and pathological status. Transmembrane mucins could contribute to lung adenocarcinoma (LUAD) proliferation, apoptosis, angiogenesis, invasion, and metastasis, and remodel the immune microenvironment involved in immune escape. Furthermore, transmembrane mucins have been explored as potential LUAD indicators for diagnosis and prognosis. The development of targeted therapy and immunotherapeutic drugs targeting transmembrane mucins has also provided broad application prospects for clinic. In the following review, we summarize the characteristic structures of diverse transmembrane mucins, regulatory roles in promoting the progression of LUAD, and the current situation of diagnosis, prognosis, and therapeutic strategies based on transmembrane mucins.

Fig. 1. The biological structure of MUC1.

The VNTR in MUC1-N consists of 20 amino acid repeats that are extensively O-glycosylated at serine and threonine residues. The structure of mucin O-glycan can be divided into four main core structures. Gal, GalNAc, Fuc, and SA residues are further added to them to extend the branches. ^*Core 1 is formed by the transfer of Gal to an O-linked GalNAc residue. ^**Core 2 is the second branch of a GalNAc residue that is formed by adding another GlcNAc to Core 1. ^***Core 3 was formed by adding GlcNAc to the GalNAc section. ^****Core 4 is a second branch of the GalNAc residue by adding another GlcNAc to Core 3.

Fig. 2. The process of activating the EGF domain of MUC4 and binding ERBB2.

MUC4 in the resting state senses changes in the extracellular environment, including extracellular ligands, ions concentration, oxygenation, and hydration. Then the subunit release and the EGF domains are exposed. The exposed EGF domains attach to ERBB2, which would prevent NSCLC cells from apoptosis.

Fig. 3. Differential signaling of MUC1 and MUC16 in LUAD pathogenesis.

MUC1 stimulates the growth of LUAD cells and prevents their death by overexpressing MYC and turning on the PI3K/AKT/mTOR pathway. MUC16 controlled the development of LUAD cells via the JAK2/STAT3/GR axis. MUC1 activates the ERK and AKT pathways to upregulate VEGF and encourage angiogenesis. MUC1 induces EMT via upregulating the expression of LIN28B and ZEB1, which then promotes LUAD cell invasion and metastasis. MUC1-C interacts with ZEB1 and NFκB/P65 to engage in immunological escape by regulating TLR-9, IFNG, MCP-1, GM-CSF, and PD-L1.