Antitumor effects of Mucin 1/sec involves the modulation of urokinase-type plasminogen activator and signal transducer and activator of transcription 1 expression in tumor cells.
Expression of the transmembrane isoform of Mucin 1 (MUC1/TM) in an aggressive murine mammary tumor line, DA-3, does not alter tumor development and metastasis, leading to death of the host. However, tumor cells expressing a secreted isoform of MUC1 (MUC1/sec) fail to develop tumors in immunocompetent mice. The rejection of MUC1/sec-expressing tumor cells is immunologically mediated, as, initially, innate cells and, ultimately, T cells are required. After gene array analysis, and confirmation at the protein level, it was discovered that MUC1/sec-expressing tumor cells (DA-3/sec) have a significant reduction in expression of urokinase-type plasminogen activator (uPA) relative to the parental tumor line and tumor cells expressing MUC1/TM. The serine protease uPA has been found to be involved in growth-promoting signaling, angiogenesis, and induction of matrix remodeling leading to metastasis. Although the tumor-promoting Stat3 transcription factor was unaltered in these tumor cells, the tumor-suppressive and IFN-responsive signal transducer and activator of transcription 1 (Stat1) is dramatically up-regulated in DA-3/sec cells. In addition, treatment of various murine and human cell lines with conditioned medium containing MUC1/sec results in up-regulation of Stat1. DA-3/sec tumor cells are also sensitized to the antiproliferative effects of IFN-gamma. Furthermore, transfection of the Stat1 gene into DA-3 tumor cells leads to a down-regulation of uPA and delays tumor progression. Thus, Stat1 up-regulation in DA-3/sec cells seems to play a significant role in the mechanism(s) by which rejection of tumor cells expressing MUC1/sec may be occurring.
Ilkovitch
Dan
D
Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, FL 33101, USA.
Handel-Fernandez
Mary Ellen
ME
Herbert
Lynn M
LM
Lopez
Diana M
DM
D000818:Animals; D015536:Down-Regulation; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018396:Mucin-1 / Q000276:immunology* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D018396:Mucin-1; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014568:Urokinase-Type Plasminogen Activator