Zhao Jiaxin, Wang Cheng, Zhao Liang, Zhou Huiying, Wu Rui, Zhang Tao, Ding Jiawei, Zhou Junjie, Zheng Huilin, Zhang Lei, Kong Tianci, Zhou Jie, Hu Zhenhua
Department of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, Zhejiang Province, People's Republic of China.
Department of Radiology, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, Zhejiang Province, People's Republic of China.
J Hepatocell Carcinoma. 2024 Apr 23;11:747-766. doi: 10.2147/JHC.S450711. eCollection 2024.
Nonsense-mediated RNA decay (NMD), a surveillance pathway for selective degradation of aberrant mRNAs, is associated with cancer progression. Its potential as a predictor for aggressive hepatocellular carcinoma (HCC) is unclear. Here, we present an innovative NMD risk model for predicting HCC prognosis.
The Cancer Genome Atlas (TCGA) data of 374 liver HCC (LIHC) and 50 normal liver samples were extracted. A risk model based on NMD-related genes was developed through least absolute shrinkage and selection operator Cox (LASSO-Cox) regression of the LIHC-TCGA data. Prognostic validation was done using GSE54236, GSE116174, and GSE76427 data. Univariate and multivariate Cox regression analyses were conducted to assess the prognostic value of the model. We also constructed nomograms for survival prediction. Tumor immune infiltration was evaluated using the CIBERSORT algorithm, and the tumor cell phenotype was assessed. Finally, mouse experiments verified UPF3B knockdown effects on HCC tumor characteristics.
We developed a risk model based on four NMD-related genes (, and ) and validated it using GSE54236, GSE116174, and GSE76427 data. The model effectively distinguished high- and low-risk groups corresponding to unfavorable and favorable HCC outcomes. Its prognostic prediction accuracy was confirmed through time-dependent ROC analysis, and clinical-use nomograms with calibration curves were developed. Single-cell RNA sequencing results indicated significantly higher expression of and in tumor cells. Knockdown of and inhibited HCC cell proliferation, invasion, and migration, while affecting cell-cycle progression and apoptosis. In vivo, knockdown delayed tumor growth and increased immune cell infiltration.
Our NMD-related gene-based risk model can help identify therapeutic targets and biomarkers for HCC. Additionally, it assists clinicians in predicting the prognosis of HCC patients.
无义介导的RNA衰变（NMD）是一种用于选择性降解异常mRNA的监测途径，与癌症进展相关。其作为侵袭性肝细胞癌（HCC）预测指标的潜力尚不清楚。在此，我们提出一种用于预测HCC预后的创新NMD风险模型。
提取374例肝脏HCC（LIHC）和50例正常肝脏样本的癌症基因组图谱（TCGA）数据。通过对LIHC-TCGA数据进行最小绝对收缩和选择算子Cox（LASSO-Cox）回归，开发了基于NMD相关基因的风险模型。使用GSE54236、GSE116174和GSE76427数据进行预后验证。进行单因素和多因素Cox回归分析以评估模型的预后价值。我们还构建了生存预测列线图。使用CIBERSORT算法评估肿瘤免疫浸润，并评估肿瘤细胞表型。最后，小鼠实验验证了UPF3B敲低对HCC肿瘤特征的影响。
我们基于四个NMD相关基因（ 、 和 ）开发了一个风险模型，并使用GSE54236、GSE116174和GSE76427数据对其进行了验证。该模型有效地区分了与不良和良好HCC结果相对应的高风险和低风险组。通过时间依赖性ROC分析证实了其预后预测准确性，并开发了带有校准曲线的临床使用列线图。单细胞RNA测序结果表明 和 在肿瘤细胞中的表达明显更高。敲低 和 可抑制HCC细胞增殖、侵袭和迁移，同时影响细胞周期进程和凋亡。在体内， 敲低可延缓肿瘤生长并增加免疫细胞浸润。
我们基于NMD相关基因的风险模型有助于识别HCC的治疗靶点和生物标志物。此外，它有助于临床医生预测HCC患者的预后。
