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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.

Abstract
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.
AuthorsDan Ilkovitch, Mary Ellen Handel-Fernandez, Lynn M Herbert, Diana M Lopez
JournalCancer research (Cancer Res) Vol. 68 Issue 7 Pg. 2427-35 (Apr 1 2008) ISSN: 1538-7445 [Electronic] United States
PMID18381451 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Mucin-1
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Urokinase-Type Plasminogen Activator
Topics
  • Animals
  • Down-Regulation
  • Mammary Neoplasms, Experimental (genetics, immunology, metabolism, pathology)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mucin-1 (immunology, metabolism)
  • STAT1 Transcription Factor (biosynthesis, genetics, immunology, metabolism)
  • Transfection
  • Urokinase-Type Plasminogen Activator (biosynthesis, genetics, immunology, metabolism)

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