Luker K E, Pica C M, Schreiber R D, Piwnica-Worms D
Department of Radiology, Washington University Medical School, St. Louis, Missouri 63110, USA.
Cancer Res. 2001 Sep 1;61(17):6540-7.
IRF9/p48/ISGF3gamma (IRF9) is an IFN regulatory factor that mediates signaling by type I IFNs (IFNalpha and IFNbeta). After single-step selection of breast adenocarcinoma cells in paclitaxel, differential display and single gene analysis demonstrated that transcriptional activation of IRF9 and other IFN-responsive genes, independent of IFN, corresponded with resistance to antimicrotubule agents. Transient overexpression of IRF9 reproduced the drug-resistance phenotype and induced expression of IFN-responsive genes. However, drug resistance was not induced by overexpression of Stat1 or Stat2, or treatment with IFNalpha per se. Using a donor-matched array of cDNA prepared from human tumor and normal tissue from a variety of organs, we observed overexpression of IRF9 in approximately one-half of breast and uterine tumors, which indicated that IRF9 may be important in signaling in these tumor types. These data identify a novel IFN-independent role for IRF9 in the development of resistance to antimicrotubule agents in breast tumor cells and may link downstream mediators of IFN signaling to drug resistance in human cancers.
IRF9/p48/ISGF3γ（IRF9）是一种干扰素调节因子，介导I型干扰素（IFNα和IFNβ）的信号传导。在紫杉醇中对乳腺癌细胞进行单步筛选后，差异显示和单基因分析表明，IRF9和其他IFN反应基因的转录激活与抗微管药物的耐药性相关，且不依赖于IFN。IRF9的瞬时过表达重现了耐药表型并诱导了IFN反应基因的表达。然而，Stat1或Stat2的过表达或单独使用IFNα处理均未诱导耐药性。使用从各种器官的人类肿瘤和正常组织制备的供体匹配cDNA阵列，我们观察到约一半的乳腺和子宫肿瘤中IRF9过表达。这表明IRF9在这些肿瘤类型的信号传导中可能很重要。这些数据确定了IRF9在乳腺肿瘤细胞对抗微管药物耐药性发展中的一种新的不依赖IFN的作用，并可能将IFN信号的下游介质与人类癌症中的耐药性联系起来。
