Abstract
MUC1 is a transmembrane glycoprotein abnormally expressed in all stages of development of human adenocarcinomas. Overexpression and hypoglycosylation of MUC1 in cancer cells compared with normal epithelial cells are likely to alter its function and affect the behavior of cancer cells. The extracellular domain, specifically the highly O-glycosylated VNTR (variable number of tandem repeats) region, plays an important role in cell-cell communication; however, we show here that it also participates intracellularly in activation of the NF-κB pathway. Transfection of MUC1(-) tumor cells with cDNA encoding MUC1 with 22 tandem repeats (MUC1/22TR) or two tandem repeats (MUC1/2TR) or two isoforms that lack the VNTR region (MUC1/Z and MUC1/Y) showed that the highest expression levels of NF-κB family members correlated with the presence of VNTR and the highest number of tandem repeats. Because expression of MUC1 with VNTR on tumors was previously associated with chemotactic activity for cells of the innate immune system, we investigated the influence of MUC1 expression on the NF-κB-dependent transcriptional regulation of proinflammatory cytokines. ChIP and real-time PCR experiments revealed that MUC1/22TR up-regulated IL-6 and TNF-α expression by binding to their promoter regions in a NF-κB p65-dependent manner in both MUC1-transfected and human breast cancer cells that express endogenous MUC1. This newly detected complex of MUC1 and p65 is a novel mechanism that tumors can use to promote inflammation and cancer development.
Highlights
Human MUC1 is overexpressed and abnormally glycosylated in adenocarcinomas, correlating with inflammation and tumor growth
We propose that abnormal expression of MUC1, known to occur early in cancer development, activates production of proinflammatory cytokines by tumor cells, leading to their accumulation in the tumor microenvironment and chronic inflammation, favoring tumor progression
Using a mouse lymphoma cell line and a human melanoma cell line activated with concanavalin A (ConA) or TNF-␣, respectively, both naturally negative for MUC1 expression, we observed that transfection with full-length MUC1 and two short MUC1 isoforms lacking the VNTR region in the extracellular domain resulted in activation of the NF-B pathway
Summary
Human MUC1 is overexpressed and abnormally glycosylated in adenocarcinomas, correlating with inflammation and tumor growth. ChIP and real-time PCR experiments revealed that MUC1/22TR up-regulated IL-6 and TNF-␣ expression by binding to their promoter regions in a NF-B p65-dependent manner in both MUC1-transfected and human breast cancer cells that express endogenous MUC1. This newly detected complex of MUC1 and p65 is a novel mechanism that tumors can use to promote inflammation and cancer development. We report the interaction of the full-length MUC1 molecule, including the VNTR-containing extracellular domain, with the NF-B pathway, which is activated in a large number of cancers and plays a role as a pivotal link between cancer and inflammation through its ability to up-regulate expression of tumor-promoting cytokines such as IL-6 and TNF-␣. We show that the extracellular domain of MUC1 localizes in the nucleus, promoting the expression of proinflammatory cytokines in tumors through a newly identified complex of full-length MUC1 and p65
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