Abstract：
We aimed to investigate the effects of tumor necrosis factor (TNF)-α on the expression of interferon α/β receptor subunit 1 (IFNAR1) and cervical squamous cancer (CSCC) resistance to Cisplatin, as well as the underlying mechanisms. Kaplan-Meier analysis was used to plot the overall survival curves. SiHa cells were treated with 20 ng/ml TNF-α to determine cell proliferation in human CSCC cells and the expression of IFNAR1. The effects of TNF-α on the downstream signaling pathway, including casein kinase 1α (CK1α), were investigated using the caspase protease inhibitor FK009, the c-Jun kinase inhibitor SP600125, and the nuclear factor kappa-B inhibitor ammonium pyrrolidinedithiocarbamate (PDTC). TNF-α induced down-regulation of IFNAR1 in human CSCC cells and promoted proliferation of SiHa cells. SiHa cells were transfected with the catalytic inactive mutant CK1α K49A, and the ability of TNF-α to induce down-regulation of IFNAR1 expression was found to be significantly diminished in this context. FK009 and PDTC had no obvious effect on the expression of CK1α, however, SP600125 significantly reduced the expression of CK1α in the presence of TNF-α. SiHa cells treated with TNF-α showed reduced sensitivity to Cisplatin and exhibited higher cell viability, while the sensitivity of SiHa cells to Cisplatin was restored after treatment with CK1α inhibitor D4476. Additionally, we constructed a TNF-α overexpressing SiHa cell line and a transplanted tumor model. The results were similar to those of in vitro efficacy. We demonstrate that TNF-α-induced down-regulation of type I interferon receptor contributes to acquired resistance of cervical squamous cancer to Cisplatin.
摘要：
我们旨在研究肿瘤坏死因子（TNF）-α对干扰素α/β受体亚基1（IFNAR1）表达和宫颈鳞癌（CSCC）对顺铂耐药的影响。以及潜在的机制。使用Kaplan-Meier分析绘制总体存活曲线。用20ng/mlTNF-α处理SiHa细胞以测定人CSCC细胞中的细胞增殖和IFNAR1的表达。TNF-α对下游信号通路的影响,包括酪蛋白激酶1α（CK1α），使用caspase蛋白酶抑制剂FK009，c-Jun激酶抑制剂SP600125和核因子κB抑制剂吡咯烷二硫代氨基甲酸铵（PDTC）进行了研究。TNF-α诱导人CSCC细胞中IFNAR1的下调并促进SiHa细胞的增殖。SiHa细胞用催化失活突变体CK1αK49A转染，在这种情况下，TNF-α诱导IFNAR1表达下调的能力显着降低。FK009和PDTC对CK1α的表达无明显影响,然而,在存在TNF-α的情况下,SP600125显著降低CK1α的表达。用TNF-α处理的SiHa细胞显示对顺铂的敏感性降低，并表现出更高的细胞活力，而用CK1α抑制剂D4476治疗后，SiHa细胞对顺铂的敏感性恢复。此外,我们构建了TNF-α过表达的SiHa细胞系和移植肿瘤模型。结果与体外功效相似。我们证明TNF-α诱导的I型干扰素受体下调有助于宫颈鳞癌对顺铂的获得性耐药。
