Xia Zicong, Zhao Wenjing, Liu Jibin, Zhang Jing, Pan Jing, Chen Kang, Wang Lele, Zhao Hui, Chen Xiaoqing
Department of Interventional Radiology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001 Jiangsu, China.
Cancer Research Center Nantong, Tumor Hospital Affiliated to Nantong University, Nantong, 226361 Jiangsu, China.
J Oncol. 2022 Sep 28;2022:2704862. doi: 10.1155/2022/2704862. eCollection 2022.
Transarterial chemoembolization (TACE) is a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). Owing to differences in its efficacy across individuals, determining the indicators of patient response to TACE and finding approaches to reversing nonresponse thereto are necessary.
Transcriptome data were obtained from the GSE104580 dataset, in which patients were marked as having TACE response or nonresponse. We identified differentially expressed genes (DEGs) and performed Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We screened genes with a prognostic value for TACE in the HIF-1 signaling pathway by univariate regression analysis. By using least absolute shrinkage and selection operator (LASSO) Cox regression, we established a multigene signature in GSE14520, which we verified using a drug sensitivity test. The Connectivity Map (CMap) database was used to find potential drugs to reverse nonresponse to TACE.
We constructed a prognostic signature consisting of three genes (erythropoietin (), heme oxygenase 1 (), and serine protease inhibitor 1 ()) that we validated by drug sensitivity test. After dividing patients treated with TACE into high- and low-risk groups based on this new signature, we showed that overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group and that the risk score was an independent predictor of OS in patients treated with TACE. Based on our CMap findings, we speculated that PD-184352, an inhibitor of mitogen-activated protein kinase (MEK), had potential as a drug treatment to reverse nonresponse to TACE. We confirmed this speculation by using PD-184352 in a cell promotion experiment in a TACE environment.
We constructed a TACE-specific three-gene signature that could be used to predict HCC patients' responses to and prognosis after TACE treatment. PD-184352 might have potential as a drug to improve TACE efficacy.
经动脉化疗栓塞术（TACE）是不可切除肝细胞癌（HCC）患者的一线治疗方法。由于个体疗效存在差异，确定患者对TACE反应的指标并找到逆转无反应的方法很有必要。
从GSE104580数据集中获取转录组数据，其中患者被标记为有TACE反应或无反应。我们鉴定了差异表达基因（DEG）并进行了京都基因与基因组百科全书（KEGG）分析。通过单变量回归分析，我们在缺氧诱导因子-1（HIF-1）信号通路中筛选出对TACE具有预后价值的基因。通过使用最小绝对收缩和选择算子（LASSO）Cox回归，我们在GSE14520中建立了一个多基因特征，并通过药物敏感性试验进行了验证。利用连接图谱（CMap）数据库寻找逆转对TACE无反应的潜在药物。
我们构建了一个由三个基因（促红细胞生成素（）、血红素加氧酶1（）和丝氨酸蛋白酶抑制剂1（））组成的预后特征，并通过药物敏感性试验进行了验证。根据这个新特征将接受TACE治疗的患者分为高风险组和低风险组后，我们发现高风险组的总生存期（OS）显著低于低风险组，并且风险评分是接受TACE治疗患者OS的独立预测因子。基于我们在CMap中的发现，我们推测丝裂原活化蛋白激酶（MEK）抑制剂PD-184352有作为逆转对TACE无反应的药物治疗的潜力。我们通过在TACE环境下的细胞增殖实验中使用PD-184352证实了这一推测。
我们构建了一个TACE特异性的三基因特征，可用于预测HCC患者对TACE治疗的反应和预后。PD-184352可能有作为提高TACE疗效药物的潜力。
