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Cancer cell development: MUC1 MAGic wand

Immunostained MUC1 in ductal adenocarcinoma of the pancreas. Luminal (apical) and intracytoplasmic staining in glandular structures.

MUC1 is a heterodimeric transmembrane glycoprotein predominantly expressed on epithelial cells and epithelium-derived cancer cells. The C-terminal subunit of MUC1 (MUC1-C) contains a small extracellular N-glycosylated domain and an intracellular domain for which mounting evidence points to a role in cell signaling. The largest part of extracellular MUC1 is the variable number of tandem repeats (VNTR) region consisting of 20-100 repeated 20mers, each possessing 5 O-glycosylation sites. Cancer cell MUC1 O-glycans are more abundant, shorter and more frequently terminated by sialic acid than glycans of wild-type cell MUC1. Swanson et al., reporting in Cancer Research, have elucidated how these changes contribute to the perineural invasion of pancreatic cancer cells, which is an early stage of cancer metastasis. At the same time in Nature Cell Biology, Ahmad et al. have now connected MUC1-C to the NF-B pathway.

Swanson et al. noticed that S2-013 pancreatic cancer cells adhered to myelin-associated glycoprotein (MAG) — also known as Siglec-4a — which is a major Schwann cell receptor that guides neurite outgrowth. Immunoprecipitation showed that MUC1 is a binding partner of MAG, and this was confirmed in MUC1-expressing Chinese hamster ovary cells. Furthermore, Swanson et al. expressed varying amounts of MAG or MUC1 to show that the strength of pancreatic cancer cell adhesion depends quantitatively upon the amount of both proteins.

S2-013 cell adhesion to MAG was abrogated when the binding assay was treated with sialidase or 5LE antibody raised against the sialyl-T antigen trisaccharide carried by cancer cell MUC1. Similarly, pancreatic cancer cells expressing a MUC1 variant lacking the VNTR region did not bind to MAG. Thus, the sialic acid cap of the sialyl-T-antigen glycan carried by the MUC1 VNTR region is required for cancer cell-Schwann cell adhesion. Lastly, the presence of MUC1 and MAG in vivo in human tissues was confirmed by immunohistochemistry.

Ahmad et al. observed that MUC1 abundance correlated with NF-B levels in cancer cells. When MUC1-C was expressed in breast cancer cells that had knocked down MUC1 expression, the authors observed an increase in the amount of inhibitor of B kinase (IKK)-IKK complex in association with MUC1-C. Phosphorylation of IB was also increased, thus amplifying the targeting of the NF-B subunit p65 to the nucleus. These findings indicate that MUC1-C is connected directly to the NF-B signaling pathway as IKK kinases phosphorylate IB, leading to the release of the NF-B subunits from the IB inhibition complex. Importantly, the authors showed that this signaling mechanism is constitutively activated in breast cancer cells, where it may contribute to cancer cell apoptosis inhibition. In contrast, normal breast epithelial cells activated the MUC1-NF-B pathway in response to the tumor necrosis factor (TNF) and other proinflammatory stimuli via recruitment of MUC1-C to the TNF receptor complex upon TNF binding.

Taken together, MUC1 in cancer cells may support both metastasis by enhanced adhesion to MAG and apoptosis evasion by constitutive NF-B activation. These results reaffirm the significance of MUC1 as a therapeutic target for cancer treatment.

Author: Mirko von Elstermann