MUC1 protein expression in tumor cells regulates transcription of proinflammatory cytokines by forming a complex with nuclear factor-κB p65 and binding to cytokine promoters: importance of extracellular domain.
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.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; Fondazione Ri.MED, Piazza Sett'Angeli, Palermo 90134, Italy. Electronic address: sac131@pitt.edu.
Sandra
S
Cascio
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
Lixin
L
Zhang
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
Olivera J
OJ
Finn
D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018396:Mucin-1 / Q000378:metabolism*; D011485:Protein Binding; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D015850:Interleukin-6; C060192:MUC1 protein, human; D018396:Mucin-1; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha