MUC16: clinical targets with great potential

Abstract

Mucin 16 (MUC16) is a membrane-bound mucin that is abnormally expressed or mutated in a variety of diseases, especially tumors, while being expressed in normal body epithelium. MUC16 and its extracellular components are often important cancer-related biomarkers. Abnormal expression of MUC16 promotes tumor progression through mesenchymal protein, PI3K/AKT pathway, JAK2/STAT3 pathway, ERK/FBW7/c-Myc, and other mechanisms, and plays an important role in the occurrence and development of tumors. In addition, MUC16 also helps tumor immune escape by inhibiting T cells and NK cells. Many drugs and trials targeting MUC16 have been developed, and MUC16 may be a new direction for future treatments. In this paper, the mechanism of action of MUC16 in the development of cancer, especially in the immune escape of tumor, is introduced in detail, indicating the potential of MUC16 in clinical treatment.

Keywords: Biomarker; CA125; Clinical trials; Immune escape; Mucin 16 (MUC16).

Fig. 1

Structure diagram of MUC16. MUC16 features three domains: N-terminal, carboxyl-terminal, and tandem repeating domain. The latter contains 16 SEA modules. The carboxyl-terminal domain includes an extracellular part, a transmembrane region, and a short cytoplasmic tail with a potential NLS, an ERM binding domain and a phosphorylated tyrosine. Both O-linked and N-linked glycosylation occurs, with the amino-terminal domain dominated by O-glycosylation

Fig. 2

Mechanism of action of MUC16 in ovarian cancer. Free CA125 binding MSLN inhibited DKK1 expression, activated SGK3/FOXO3a pathway, and MUC16 binding MSLN on cell surface promoted epithelial ovarian cancer metastasis. High expression of MUC16 can promote the development of ovarian cancer through Foxo3a, Bcl-2, GLUT1, E-cadherin, P120ctn/RhoA, and PI3K/AKT/pS6.CircMUC16 modulates autophagy by sponging miR-199a-5p to enhance Beclin1 and RUNX1 expression, reciprocally regulated by RUNX1, and directly interacts with ATG13 to influence ATG13 expression

Fig. 3

Mechanism of action of MUC16 in pancreatic cancer. Interacting with Mesothelin, MUC16 enhances MMP7 expression via p38MAPK phosphorylation. Sialosylated MUC16 binds E- and L-selectin, promoting adhesion to host tissues. galectin binding facilitates PDAC cell metastasis.MUC16-Cter induces JAK2 nuclear shift, upregulating LMO2 and NANOG. Cytoplasmic MUC16c release activates IL-6 secretion through JAK2/STAT3.Cytoskeletal proteins (Actg2, MYH11, Pdlim3) are upregulated, altering the tumor microenvironment. NRP2 upregulation via JAK2/STAT1 promotes metastasis.MUC16 binds FAK, activating downstream AKT and ERK/MAPK. Truncated O-glycochains interact with integrins, activating ILK.c-Myc regulates MUC16 expression transcriptionally, and forming a feedback loop.MiR-29a antagonizes MUC16-mediated migration and invasion

Fig. 4

Mechanism of action of MUC16 in non-small cell lung cancer, interstitial lung disease and corneal epithelial infection. In NSCLC, ERO1L influences IL6R secretion, activating NF-κB, and promoting MUC16 expression. MUC16, in turn, regulates TSPYL5 via JAK2/STAT3/GR, impacting p53 expression. In interstitial lung disease, TGF-β1-induced MUC16 complexes with pSmad3 drive fibroblast proliferation and cellular transformation. Conversely, in corneal epithelial cells, MUC16 inhibits pro-inflammatory cytokines via TLR2/TLR5. HAdV-D37 compromises MUC16's protective barrier to facilitate infection

Fig. 5

The mechanism of MUC16 in cholestatic hepatic fibrosis. In wild type (WT) aPFs in cholestatic fibrosis, Thy-1 and MUC16 interact with TGFβRI, MUC16, and Thy-1 bind to MSLN (but not to each other), and SMAD7 binds to the complex. TGF-β1 exposure triggers the separation of Thy-1 and MUC16 from TGF-βri, promoting COL1A1 expression. In Msln-/ -APF, the absence of Msln increases the formation of the inhibitory Thy-1-TGFβRI complex and blocks the expression of COL1A1. Fgf-induced pathways differ, with impaired AKT phosphorylation, impaired compensatory ERK1/2 phosphorylation, and altered JAK2/STAT3 activation

Fig. 6

MUC16-mediated inhibition of NK cells in epithelial ovarian cancer. Shed MUC16 (sMUC16) binds to NK cells via Siglec-9, initiating immune suppression prior to NK cell tumor-killing. Cell surface MUC16 (csMUC16) reduces NK cell-cancer cell proximity, diminishing their binding and impairing NK cell-mediated tumor cell killing