Mucins (MUC) are high-molecular-weight glycoproteins primarily secreted by epithelial cells in the form of mucus. They play critical roles in maintaining epithelial barrier integrity, protecting tissues from environmental insults, regulating cell adhesion, and signaling. Recent research has revealed that mucins are involved in various diseases, especially cancers, where abnormal expression of mucins is closely related to tumor progression and metastasis. Consequently, the MUC gene family is emerging as a promising target for cancer immunotherapy.

The MUC gene family comprises 22 members and is broadly classified into two main categories based on structure and function: membrane-bound and secretory mucins. This classification reflects their cellular localization and functional differences in physiological and pathological states.

Membrane-Bound Mucins

Membrane-bound mucins have type I transmembrane structures and are primarily located on the surface of epithelial cells. These mucins are embedded in the cell membrane through their transmembrane domains, forming stable adhesion structures and participating in cell-cell adhesion, signaling, and polarity maintenance. Abnormal expression of membrane-bound mucins in tumors is often associated with tumor invasion and metastasis.

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MUC1: MUC1 is a significant member of the membrane-bound mucin family and is widely expressed in the respiratory, gastrointestinal, urogenital tracts, and other epithelial tissues. The structure of MUC1 includes an extracellular mucin domain, a transmembrane domain, and a cytoplasmic domain. In normal cells, MUC1 is primarily located at the apical surface, serving as a physical barrier to protect epithelial cells. However, in cancer cells, MUC1 is often overexpressed and redistributed from the apical surface to the entire cell surface, playing a role in tumor cell proliferation, migration, and metastasis. Abnormal glycosylation of MUC1 further contributes to these processes.

MUC4: MUC4 is another important membrane-bound mucin expressed on the surface of epithelial cells. Its structure includes a long mucin domain, a transmembrane domain, and a shorter cytoplasmic domain. Changes in glycosylation of MUC4 significantly impact tumor cell proliferation and migration. MUC4 is overexpressed in various cancers, including breast and pancreatic cancer, and promotes tumor invasion and metastasis.

MUC16: MUC16 (also known as CA125) is a highly glycosylated membrane-bound mucin expressed predominantly in ovarian epithelial cells and other epithelial tissues. The extensive glycosylation of MUC16 is often abnormal in tumors, affecting tumor cell adhesion and migration. Overexpression of MUC16 is closely associated with ovarian cancer, and its serum levels are used as a marker for ovarian cancer.

MUC17: MUC17, a relatively recently discovered membrane-bound mucin, is primarily expressed in intestinal epithelial cells. Changes in glycosylation and expression levels of MUC17 are significant in inflammation and cancer. MUC17 enhances the mucosal barrier of the intestine and promotes inflammation healing. Its deficiency is associated with the early onset of colon cancer, and its role in gastric cancer has also garnered attention.

Secretory Mucins

Secretory mucins typically lack transmembrane domains and are secreted into the extracellular space, forming a protective mucous layer over epithelial cells. These mucins primarily protect epithelial tissues from harmful substances by forming a physical barrier.

MUC2: MUC2 is one of the most representative secretory mucins, mainly expressed in intestinal epithelial cells. Its glycosylation state is crucial for its function, as it forms a mucous layer to protect the intestinal epithelium and maintain integrity. Reduced expression of MUC2 is observed in inflammatory bowel disease and colon cancer, highlighting its role in maintaining intestinal barrier function.

MUC5AC: MUC5AC is predominantly expressed in the gastric and respiratory epithelial cells. Similar to MUC2, MUC5AC forms a mucous layer to protect the gastric mucosa and respiratory epithelium from pathogens and harmful substances. Abnormal expression of MUC5AC is associated with gastric inflammation and chronic bronchitis. Overexpression of MUC5AC in certain tumors may promote tumor cell proliferation and migration.

MUC5B: MUC5B is mainly found in the respiratory and gastric epithelial cells. Like MUC5AC, it protects epithelial tissues by forming a mucous layer and maintaining tissue health. Abnormal expression of MUC5B in chronic bronchitis and lung diseases has been widely studied, suggesting its role in disease development.

MUC6: MUC6 is primarily expressed in gastric epithelial cells, where it protects by forming a protective mucous layer. Changes in MUC6 expression are associated with the occurrence and progression of gastric cancer. Its glycosylation status affects its function, and abnormal glycosylation can disrupt the gastric mucosal barrier, contributing to gastric cancer.

MUC7: MUC7 is found mainly in the salivary glands, where it contributes to the formation of the mucous layer in the oral cavity. It plays a role in oral mucosal protection, including antimicrobial and lubricating functions. Abnormal expression of MUC7 in certain oral diseases and tumors suggests its potential role in these conditions.

MUC8: MUC8 is less studied in tumors, but as a secretory mucin, it may contribute to epithelial cell protection and repair. Changes in MUC8 expression in various cancers could provide insights into its potential role in tumor development.

MUC9: MUC9 is expressed in the respiratory epithelial cells and protects the respiratory tract from pathogens and harmful substances by forming a mucous layer. Abnormal expression of MUC9 may be associated with respiratory diseases and tumor development.

MUC19: MUC19 is primarily found in the eyes and salivary glands. It maintains eye health and prevents infections by forming a protective mucous layer. Abnormal expression of MUC19 may be related to eye diseases and some types of cancer.

Functions of Mucins in Cancer

Under normal physiological conditions, mucins are primarily located on the apical surface of epithelial cells and play protective and lubricating roles. However, in cancer cells, mucin expression often becomes abnormal. These changes include overexpression, abnormal glycosylation, and changes in membrane localization, which are closely related to tumor occurrence, progression, and metastasis.

For example, MUC1 is normally localized at the apical surface of cells and protects epithelial cells. In cancer cells, MUC1 is often overexpressed and redistributed across the entire cell surface. Abnormal glycosylation of MUC1 also contributes to tumor cell proliferation, migration, and metastasis by activating downstream signaling pathways.

Mucins play a critical role in tumor immune evasion. Abnormal expression of membrane-bound mucins like MUC1 can inhibit the host immune system's ability to recognize and eliminate tumor cells. MUC1, for instance, can interact with NK cells and CTLs (cytotoxic T lymphocytes), suppressing their killing activity and enhancing tumor cell immune evasion.

Similarly, overexpression of MUC4 can modulate immune cell functions and impact tumor cell immune evasion. Abnormal glycosylation of MUC4 alters tumor cell surface antigens, reducing immune system recognition. Targeting MUC4 with immune therapies has shown promise in enhancing tumor immune response and improving treatment outcomes.

Due to their widespread abnormal expression in tumors and their key role in immune evasion, mucins are emerging as promising targets in cancer immunotherapy. Targeting mucins can involve strategies such as mucin vaccines, monoclonal antibodies, and CAR-T cell therapies, which have shown significant therapeutic effects in various tumor models.

Figure. 1. Immunomodulation by tumor-associated mucins. (Bhatia R, et al., 2019)

MUC1-Targeted Immunotherapy

MUC1, a major membrane-bound mucin, has abnormally high expression in various tumors, making it a significant target for immunotherapy. Current strategies include MUC1 vaccines, MUC1 monoclonal antibodies, and MUC1-CAR-T cell therapies. These therapies aim to target MUC1, suppressing tumor cell proliferation and migration while enhancing the host immune system's ability to clear tumor cells.

MUC1 vaccines stimulate the host immune system to produce immune responses against MUC1 antigens, leading to specific tumor cell destruction. MUC1 monoclonal antibodies directly bind to MUC1, blocking its interaction with downstream signaling pathways and inhibiting tumor cell growth and metastasis. MUC1-CAR-T cell therapy involves modifying T cells to specifically target MUC1 antigens, enhancing tumor cell killing.

MUC4-Targeted Immunotherapy

MUC4's abnormal expression in breast, pancreatic, and other cancers makes it another important target. Strategies include MUC4 monoclonal antibodies and MUC4 vaccines, which aim to specifically recognize MUC4 antigens, inhibit tumor cell proliferation and migration, and improve treatment efficacy.

MUC17-Targeted Therapy

MUC17's abnormal expression in gastric and colon cancers has attracted significant research attention. Targeting MUC17 may involve MUC17 monoclonal antibodies and vaccines. These strategies could help modulate MUC17 expression, enhance mucosal barrier function, and inhibit tumor cell invasion and metastasis, offering new approaches for targeted therapy in gastric and other cancers.

The MUC gene family, with its abnormal expression and critical role in tumor immune evasion, represents a promising target in cancer immunotherapy. Further research into the mechanisms of mucin function in tumors may lead to new breakthroughs in cancer treatment.