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首页> 外文期刊>Journal of Korean medical science. >Involvement of the TNF-α Pathway in TKI Resistance and Suggestion of TNFR1 as a Predictive Biomarker for TKI Responsiveness in Clear Cell Renal Cell Carcinoma
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Involvement of the TNF-α Pathway in TKI Resistance and Suggestion of TNFR1 as a Predictive Biomarker for TKI Responsiveness in Clear Cell Renal Cell Carcinoma

机译：TNF-α通路在透明细胞肾细胞癌中TNF-α通路在TKI抗性和TNFR1中TNFR1的建议

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Background Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated. Methods We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases. Results TNFRSF1A gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression ( 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort. Conclusion TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.
机译：背景技术和预测生物标志物对先进的透明细胞肾细胞癌（CCRCC）的抗酪氨酸激酶抑制剂（TKI）抗性尚未得到完全评估。方法对来自抗牛皮治疗的10例TKI处理的CCRCC患者组成的采用TKI抗性群体进行了基因表达分析，该患者组成的10例TKI治疗的CCRCC患者，其在预处理和TKI耐药后期收获的匹配肿瘤组织。此外，还检索来自患者衍生的TKI处理的CCRCC（GSE76068）的患者衍生的异种移植模型的公共微阵列数据集。通过常规调节的不同表达基因（DEGS）来研究数据集之间的常见途径。通过免疫组织化学在单独的101型TKI处理的CCRCC病例中评估候选DEG对内在TKI抗性的重要性。结果TNFRSF1A基因表达和肿瘤坏死因子（TNF）-α途径在CCRCC中具有在微阵列数据集中获得的TKI抗性的CCRCC。另外，TNF受体1（TNFR1）的高表达（标记肿瘤细胞的10％）与TNFRSF1A基因的蛋白质产物与SarcomaToid Deffifeiation相关，并且是临床不利反应的独立预测因素，并且分离的TKI中较短的幸存者处理的CCRCC队列。结论TNF-α信号传导可能在TKI抗性中发挥作用，TNFR1表达可以用作CCRCC中的临床不利的TKI反应的预测生物标志物。

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