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

作者：Ilkovitch Dan; Handel Fernandez Mary Ellen; Herbert Lynn M; Lopez Diana M^*

来源：Cancer Research, 2008, 68(7): 2427-2435.

DOI：10.1158/0008-5472.CAN-07-5651

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/see cells seems to play a significant role in the mechanism(s) by which rejection of tumor cells expressing MUC1/sec may be occurring.

• 出版日期2008-4-1