Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells
Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells
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DOI：
10.4049/jimmunol.172.6.3922
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发表时间：
2004-03-15
影响因子：
4.4
通讯作者：
Watanabe, N
中科院分区：
文献类型：
--
作者：
Asanuma, K;Tsuji, N;Watanabe, N
癌细胞被认为具有逃避宿主免疫监视系统的机制。Survivin是一种由癌细胞过度表达的凋亡相关蛋白家族成员，可抑制免疫细胞诱导的Fas介导的凋亡。此外，癌细胞在其表面表达Fas配体（FasL）作为对免疫细胞的反击。癌细胞表达FasL的机制，包括生存素的参与，尚不清楚。在本研究中，我们证明了生存素上调FasL的表达，并研究了这可能是如何发生的。免疫组化结果显示，结肠癌组织中Survivin与FasL蛋白表达呈显著正相关（r = 0.79）。转染survivin基因的LS 180结肠癌细胞FasL表达上调。转染子显示出对Fas敏感的人T白血病细胞系Jurkat的细胞毒性增加。与此相反，FasL表达下调SW 480细胞转染一个小的抑制性RNA，以防止生存素的表达。Survivin基因转染显示转录因子特异性蛋白1（Sp1）与FasL启动子的DNA结合增加，并且在丝氨酸和苏氨酸残基处上调Sp1磷酸化; Sp1的总量不变。因此，生存素使癌细胞不仅能够通过抑制Fas介导的凋亡信号传导来抑制免疫细胞攻击，而且能够通过诱导FasL来攻击免疫细胞。
Cancer cells are thought to possess mechanisms for evading the host's immune surveillance system. Survivin, a member of the inhibitor-of-apoptosis family overexpressed by cancer cells, inhibits Fas-mediated apoptosis induced by immune cells. In addition, cancer cells express Fas ligand (FasL) on their surfaces as a counterattack against immune cells. Mechanisms by which cancer cells express FasL, including involvement of survivin, are unclear. In the present study, we demonstrated that survivin up-regulated FasL expression and investigated how this might occur. Quantitative immunostaining showed correlation between survivin and FasL protein expression in colon cancer tissues (r = 0.79). FasL expression was up-regulated in LS180 colon cancer cells transfected with the survivin gene. Transfectants showed increased cytotoxicity against a Fas-sensitive human T leukemia cell line, Jurkat. In contrast, FasL expression was down-regulated in SW480 cells transfected with a small inhibitory RNA to prevent survivin expression. Survivin gene transfectants showed increased DNA binding of transcription factor specificity protein 1 (Sp1) to the FasL promoter, and up-regulation of Sp1 phosphorylation at serine and threonine residues; the total amount of Sp1 was unchanged. Thus, survivin enables cancer cells not only to suppress immune cell attack by inhibiting Fas-mediated apoptotic signaling, but to attack immune cells by induction of FasL.