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

Dan Ilkovitch, Mary Ellen Handel-Fernandez, Lynn M. Herbert, Diana M Lopez

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 upregulated 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-γ. 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.

Original languageEnglish
Pages (from-to)2427-2435
Number of pages9
JournalCancer Research
Volume68
Issue number7
DOIs
StatePublished - Apr 1 2008

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STAT1 Transcription Factor
Mucin-1
Urokinase-Type Plasminogen Activator
Neoplasms
Protein Isoforms
Up-Regulation
Neoplasm Metastasis
Serine Proteases
Conditioned Culture Medium
Tumor Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Ilkovitch, Dan; Handel-Fernandez, Mary Ellen; Herbert, Lynn M.; Lopez, Diana M.

In: Cancer Research, Vol. 68, No. 7, 01.04.2008, p. 2427-2435.

Research output: Contribution to journalArticle

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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 upregulated 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-γ. 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.",
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