Impaired alpha-interferon signaling in transitional cell carcinoma: lack of p48 expression in 5637 cells.
Impaired alpha-interferon signaling in transitional cell carcinoma: lack of p48 expression in 5637 cells.
复制标题
移行细胞癌中的 α-干扰素信号传导受损：5637 细胞中缺乏 p48 表达。
作者：
S. Matin;R. Rackley;P. Sadhukhan;Myung;A. Novick;S. Bandyopadhyay
IFN-α治疗移行细胞癌（TCC）的临床治疗有限的成功促使我们研究TCC细胞系对IFN-α的反应性。在原代人尿路上皮细胞中，对IFN-α的反应在561基因诱导、含有IFN-α/β诱导基因的IFN-刺激的反应元件和IFN-刺激的基因因子3（ISGF 3）形成方面是正常的。我们测试了IFN-α在三个TCC系中的抗增殖作用作为IFN-α反应性的量度，并且在三个TCC系中观察到可变的生长抑制模式。超过90%的生长抑制，注意到在TCC细胞，而只有40%和10%的抑制IFN-α中观察到的5637和HT 1197细胞，分别。在电泳迁移率变动测定中，IFN-α处理在后两种相对不敏感的细胞中形成极低水平的ISGF 3。此外，通过北方印迹，561基因的表达在这两个TCC系中显著降低。我们进一步鉴定了与其他两种TCC相比，HT 1197细胞中Tyk 2的低表达水平。这表明IFN-α处理后极低的ISGF 3水平可能是由于低Tyk 2表达或其他未鉴定的缺陷。在5637细胞中，未检测到p48蛋白表达。这种不可检测的p48表达不是由于编码区的缺失，因为在IFN-γ处理后检测到正确大小的蛋白质。因此，通过IFN-γ预处理加IFN-α处理恢复了ISGF 3复合物形成和561基因诱导。将p48表达质粒导入5637细胞中足以通过IFN-α处理形成ISGF 3复合物，表明缺陷在于5637细胞中p48蛋白的表达。对IFN在膀胱癌细胞系中作用的详细机制理解可以解释IFN-α在TCC的临床治疗中消除的治疗反应。
The limited success of IFN-alpha therapy for clinical treatment of transitional cell carcinoma (TCC) has prompted us to investigate the responsiveness of TCC lines to IFN-alpha. The response to IFN-alpha in terms of 561 gene induction, an IFN-stimulated response element-containing IFN-alpha/beta-inducible gene, and IFN-stimulated gene factor 3 (ISGF3) formation was normal in primary human urothelial cells. We tested the antiproliferative effects of IFN-alpha in three TCC lines as a measure of IFN-alpha responsiveness, and variable patterns of growth inhibition were observed in three TCC lines. More than 90% growth inhibition was noted in TCCSUP cells, whereas only 40% and 10% inhibition by IFN-alpha was observed in 5637 and HT1197 cells, respectively. IFN-alpha treatment formed extremely low levels of ISGF3 in electrophoretic mobility shift assays in these later two relatively insensitive cells. In addition, expression of the 561 gene was significantly reduced in these two TCC lines by Northern blots. We have further identified a low expression level of Tyk2 in HT1197 cells compared with two other TCCs. This suggests that an extremely low ISGF3 level after IFN-alpha treatment may be due to low Tyk2 expression or other unidentified defects. In 5637 cells, p48 protein expression was undetectable. This undetectable p48 expression is not due to a deletion in the coding region because the correct size protein is detected following IFN-gamma treatment. Consequently, the ISGF3 complex formation and 561 gene induction were restored by IFN-gamma pretreatment plus IFN-alpha treatment. Introduction of p48 expressing plasmid into 5637 cells was sufficient to form the ISGF3 complex by IFN-alpha treatment, suggesting the defect lies in the expression of p48 protein in 5637 cells. Detailed mechanistic understanding of the action of IFNs in bladder cancer cell lines may explain the abrogated therapeutic response of IFN-alpha in the clinical treatment of TCCs.
影响因子：
11.2
作者：
C. Dinney;D. Bielenberg;P. Perrotte;R. Reich;B. Eve;C. Bucana;I. Fidler
通讯作者：
C. Dinney;D. Bielenberg;P. Perrotte;R. Reich;B. Eve;C. Bucana;I. Fidler