丝裂原激活蛋白激酶 (MAPK)，特别是 c-Jun N 末端激酶 (JNK)-MAPK 亚家族，在包括肝细胞癌 (HCC) 在内的各种癌症的发展中发挥着至关重要的作用。然而，JNK1/2及其上游调控因子MKK4/7在HCC癌变中的具体作用仍不清楚。本研究利用TCGA和HPA数据库对JNK-MAPK成分在转录组和蛋白水平上进行差异表达分析。我们利用 Kaplan-Meier 生存图和受试者工作特征 (ROC) 曲线分析来评估基于 TCGA-HCC 队列中这些组成部分的风险评分模型的预后性能。此外，我们还进行了免疫印迹、FACS 细胞凋亡分析和软琼脂测定，以研究 HCC 细胞系中 JNK-MAPK 通路成分对各种死亡刺激（TRAIL、TNF-α、茴香霉素和依托泊苷）的反应。JNK1/2 和 MKK7与癌旁组织相比，HCC 样本中 MKK4 的水平显着上调，而 MKK4 则下调。 ROC 分析表明 JNK2 和 MKK7 可能作为 HCC 的合适诊断基因，并且 JNK2 高表达与显着较差的总体生存率相关。 JNK1 的敲低增强了 TRAIL 诱导的肝癌细胞凋亡，而 JNK2 敲低则减少了 TNF-α/放线菌酮 (CHX) 和茴香霉素诱导的细胞凋亡。 JNK1 和 JNK2 敲低都不影响依托泊苷诱导的细胞凋亡。此外，MKK7 敲低增强了 TNF-α/CHX 和 TRAIL 诱导的细胞凋亡，并抑制肝癌细胞中的集落形成。靶向 MKK7，而不是 JNK1/2 或 MKK4，可能是抑制 HCC 中 JNK-MAPK 通路的有前途的治疗策略© 2023。作者获得施普林格自然旗下 Springer-Verlag GmbH 德国公司的独家许可。

Mitogen-activated protein kinases (MAPK), specifically the c-Jun N-terminal kinase (JNK)-MAPK subfamily, play a crucial role in the development of various cancers, including hepatocellular carcinoma (HCC). However, the specific roles of JNK1/2 and their upstream regulators, MKK4/7, in HCC carcinogenesis remain unclear.In this study, we performed differential expression analysis of JNK-MAPK components at both the transcriptome and protein levels using TCGA and HPA databases. We utilized Kaplan-Meier survival plots and receiver operating characteristic (ROC) curve analysis to evaluate the prognostic performance of a risk scoring model based on these components in the TCGA-HCC cohort. Additionally, we conducted immunoblotting, apoptosis analysis with FACS and soft agar assays to investigate the response of JNK-MAPK pathway components to various death stimuli (TRAIL, TNF-α, anisomycin, and etoposide) in HCC cell lines.JNK1/2 and MKK7 levels were significantly upregulated in HCC samples compared to paracarcinoma tissues, whereas MKK4 was downregulated. ROC analyses suggested that JNK2 and MKK7 may serve as suitable diagnostic genes for HCC, and high JNK2 expression correlated with significantly poorer overall survival. Knockdown of JNK1 enhanced TRAIL-induced apoptosis in hepatoma cells, while JNK2 knockdown reduced TNF-α/cycloheximide (CHX)-and anisomycin-induced apoptosis. Neither JNK1 nor JNK2 knockdown affected etoposide-induced apoptosis. Furthermore, MKK7 knockdown augmented TNF-α/CHX- and TRAIL-induced apoptosis and inhibited colony formation in hepatoma cells.Targeting MKK7, rather than JNK1/2 or MKK4, may be a promising therapeutic strategy to inhibit the JNK-MAPK pathway in HCC therapy.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.