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
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
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DOI：
10.1158/0008-5472.can-07-5651
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发表时间：
2008-04-01
期刊：
影响因子：
11.2
通讯作者：
Lopez, Diana M.
中科院分区：
文献类型：
--
作者：
Ilkovitch, Dan;Handel-Fernandez, Mary Ellen;Lopez, Diana M.
粘蛋白 1 (MUC1/TM) 跨膜亚型在侵袭性小鼠乳腺肿瘤系 DA-3 中的表达不会改变肿瘤的发育和转移，从而导致宿主死亡。然而，表达分泌型 MUC1（MUC1/秒）的肿瘤细胞无法在免疫功能正常的小鼠中形成肿瘤。表达 MUC1/sec 的肿瘤细胞的排斥是免疫介导的，因为最初需要先天细胞，最终需要 T 细胞。经过基因芯片分析和蛋白质水平的确认，发现表达MUC1/sec的肿瘤细胞（DA-3/sec）相对于亲本肿瘤系和表达MUC1/TM的肿瘤细胞，尿激酶型纤溶酶原激活剂（uPA）的表达显着降低。丝氨酸蛋白酶 uPA 被发现参与生长促进信号传导、血管生成和诱导导致转移的基质重塑。尽管肿瘤促进 Stat3 转录因子在这些肿瘤细胞中未发生改变，但肿瘤抑制和 IFN 响应信号转导器和转录激活剂 1 (Stat1) 在 DA-3/sec 细胞中显着上调。此外，用含有 MUC1/秒的条件培养基处理各种小鼠和人类细胞系会导致 Stat1 上调。 DA-3/秒肿瘤细胞也对 IFN-γ 的抗增殖作用敏感。此外，将 Stat1 基因转染到 DA-3 肿瘤细胞中会导致 uPA 下调并延缓肿瘤进展。因此，DA-3/see 细胞中 Stat1 的上调似乎在表达 MUC1/sec 的肿瘤细胞排斥可能发生的机制中发挥着重要作用。
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.