MUC4

Official Full Name

mucin 4, cell surface associated

Organism

Homo sapiens

GeneID

4585

Background

The major constituents of mucus, the viscous secretion that covers epithelial surfaces such as those in the trachea, colon, and cervix, are highly glycosylated proteins called mucins. These glycoproteins play important roles in the protection of the epithelial cells and have been implicated in epithelial renewal and differentiation. This gene encodes an integral membrane glycoprotein found on the cell surface, although secreted isoforms may exist. At least two dozen transcript variants of this gene have been found, although for many of them the full-length transcript has not been determined or they are found only in tumor tissues. This gene contains a region in the coding sequence which has a variable number (>100) of 48 nt tandem repeats. [provided by RefSeq, Jul 2008]

Synonyms

ASGP; MUC-4; HSA276359;

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Detailed Information

MUC4 was originally discovered in highly metastatic rat breast cancer, also known as the salivary protein complex (SMC). MUC4 is a member of the transmembrane mucin family and has a molecular weight of approximately 930 kDa. It is the largest of the transmembrane mucin family known to be structurally composed of O-glycosylated mucin subunits (ASGP-1). And the N-glycosylation transmembrane subunit (ASGP-2) consists of two subunits; the former is an extracellular structure and includes three 125 amino acid repeats; the latter is a transmembrane structure, including two EGFs a domain, a transmembrane region, and a shorter cytoplasmic tail. The latter EGF-like domain binds specifically to the EGFR family of proteins and plays a role in a variety of cellular signaling.

Figure 1. Eight shRNAs for the MUC4 gene (MUC4-shRNA) were designed and integrated into lentiviral vectors. The most efficient lentivirus for MUC4 mRNA interference was chosen for stable MUC4 knockdown in BxPC-3 cells. (Li, Y., et al. 2016)

MUC4 and Intercellular Adhesion

MUC4 can block the adhesion of foreign substances to the cell surface and regulate the adhesion between cells. In normal epithelial cells, this mechanism protects cells from microbial invasion. In pancreatic cancer cells, MUC4 can inhibit cell assembly. Similarly, MUC4 also protects tumor cells from immune cells, even the killing of antibody molecules that specifically bind to the cell surface, thus blocking the immune surveillance of tumor cells. Studies have found that overexpression of MUC4 in breast cancer cells treated with trastuzumab, silencing MUC4 expression can repair the binding of trastuzumab to tumor cells.

The effect of MUC4 on intercellular adhesion may be closely related to the location of MUC4 on the cell surface. In polarized epithelial cells, MUC4 is distributed on the upper surface of the cell, while in depolarized tumor cells, MUC4 is distributed throughout the cell surface. In tumors, MUC4 is able to dissociate the adhesion between cells and detach the cells from the primary tumor, which is beneficial to the invasion and metastasis of tumor cells. Dissociation of intercellular adhesions and cadherin cross-linking can disrupt cell-to-cell contact inhibition and activate the extracellular signal-regulated kinase (ERK) pathway to promote tumor cell proliferation. Therefore, MUC4 can promote the growth of tumor cells through an anti-cell adhesion mechanism.

Regulation of MUC4 in Tumors

MUC4 is not expressed in normal pancreatic tissue and is highly expressed in pancreatic cancer tissues, so it can be used as a potential target for the treatment of pancreatic cancer. Although direct targeting of mucins is difficult, they are easily blocked by small molecule inhibitors because they are inactive, so mucin expression can be inhibited by small molecule inhibitors. Retinoic acid, IFN-γ and TGFβ have been shown to be transcription factors of MUC4. TGFβ includes both SMAD-dependent and non-dependent pathways, and is negatively regulated by SMAD7. STAT-1 is regulated by IFN-γ, and in pancreatic cancer cell lines, INF and retinoic acid up-regulate the expression of MUC4 in a synergistic manner. TNF and IFN-γ also activate STATs and nuclear factor κB in a synergistic manner, and the latter two bind to the MUC4 promoter to initiate transcription, thereby enhancing MUC4 expression.

Interleukins are also involved in the regulation of MUC4. Studies have shown that interleukins (IL-2 and IL-9) are involved in the regulation of MUC4 through the JAK-STAT pathway in normal tracheal tissues, and such mechanisms exist in lung cancer cell lines. In addition, studies have shown that the STAT pathway is involved in the upregulation of MUC4 by IL-6 in gastric cancer. In some tumors, epigenetics is also involved in the regulation of MUC4.

References:

Li, Y. , Wu, C. , Chen, T. , Zhang, J. , Liu, G. , & Pu, Y. , et al. (2016). Effects of rnai-mediated muc4 gene silencing on the proliferation and migration of human pancreatic carcinoma bxpc-3 cells. Oncology Reports.
Nabatchian, F. , Rahimi Naiini, M. , Moradi, A. , Tabatabaeian, H. , Hoghoughi, N. , & Azadeh, M. , et al. (2018). Mir-581-related single nucleotide polymorphism, rs2641726, located in muc4 gene, is associated with gastric cancer incidence. Indian Journal of Clinical Biochemistry.
Lee, H. H., Lee, S. R., & Leem, S. H. (2014). Abstract 2335: thymoquinone induces the muc4 mrna-destabilizing activity of tristetraprolin. Cancer Research, 74(19 Supplement), 2335-2335.

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