KIF4A在肝细胞癌中的表达及预后价值分析

背景与目的:肝细胞癌(HCC)是原发性肝癌最常见的病理类型,其起病隐匿,预后较差,位居癌症相关死亡原因第3位。KIF4A在多种恶性肿瘤中呈高表达且与不良预后密切相关,然而其在HCC中的作用及机制尚不清楚。因此,本研究分析KIF4A基因在HCC中的表达情况及预后价值,并探讨相关的分子机制。方法:从癌症基因组图谱(TCGA)下载获取HCC相关的表达数据和临床参数,使用R语言和Perl包等软件分析KIF4A在正常肝组织、HCC组织中的表达水平及其与临床病理特征的关系。采用Kaplan-Meier生存分析方法和随时间变化的ROC曲线评估KIF4A在HCC中的预后价值;单因素和多因素Cox回归分析用于预测影响HCC患者预后的危险因素。纳入相关临床病理因素,使用R软件构建预测肝癌患者预后的列线图。采用免疫组化法验证KIF4A在HCC组织及其对应癌旁组织的临床标本中的表达水平;GSEA富集分析用于探讨KIF4A在HCC中可能调控的分子信号通路。结果:KIF4A在HCC组织中的表达水平明显高于正常肝组织(P<0.001),且KIF4A高表达患者的总体生存时间(OS)明显短于低表达患者(P=0.002),ROC曲线1、3、5年OS的曲线下面积(AUC)依次为0.783、0.662、0.574。肿瘤临床分期(HR=2.084,95%CI=1.590~2.733,P<0.001)、T分期(HR=1.980,95%CI=1.541~2.543,P<0.001)和KIF4A表达水平(HR=1.113,95%CI=1.062-1.167,P<0.001)与患者OS明显有关,且KIF4高表达(HR=1.089,95%CI=1.034-1.147,P=0.001)是HCC患者预后的独立危险因素。列线图结果显示KIF4A表达水平对总分值有显著影响,而其他临床病理因素对总评分的影响相对较小。免疫组织化学检测证实KIF4A在HCC组织中呈阳性表达,而在癌旁肝组织中呈弱阳性或阴性表达;GSEA富集分析结果提示KIF4A可能参与调控碱基切除修复、细胞周期、DNA复制、错配修复、m TOR信号通路、核酸切除修复、P53信号通路、癌症通路、磷脂酰肌醇信号传导等9条信号通路。结论:KIF4A在HCC组织中呈高表达,与HCC患者的肿瘤临床分期、组织学分级以及生存预后密切相关,并参与调控多条肿瘤相关信号通路,提示KIF4A可能是HCC患者预后预测和靶向治疗的潜在分子标志物。

Expression of KIF4A in hepatocellular carcinoma and its prognostic value

Background and Aims: Hepatocellular carcinoma(HCC) is the most prevalent primary liver cancer,with insidious onset and poor prognosis, and ranks the third leading cause of cancer-related deaths worldwide. KIF4 A is highly expressed in a variety of malignancies and strongly associated with poor prognosis. However, the role and mechanism underlying KIF4 A in HCC remain unclear. Therefore, this study was conducted to investigate the expression and prognostic value of KIF4 A in HCC, and the associated mechanism.Methods: The expression data and clinical parameters associated with HCC were obtained from the Cancer Genome Atlas(TCGA) and the expression levels of KIF4 A in HCC and its relationship with clinicopathologic features were analyzed using software such as R language and Perl package. The prognostic value of KIF4 A in HCC was evaluated by the Kaplan-Meier survival analysis and timedependent ROC curves. The independent risk factors for the prognosis of HCC patients were determined by univariate and multivariate Cox regression analysis. A nomogram for predicting the prognosis of HCC patients was constructed by including relevant clinicopathologic factors using R software.Immunohistochemical staining was performed to verify the expression levels of KIF4 A in the clinical specimens of HCC tissues and their adjacent noncancerous tissues. The molecular signaling pathways potentially regulated by KIF4 A in HCC were analyzed by GSEA enrichment analysis.Results: The expression level of KIF4 A in HCC tissues was significantly higher than that in normal liver tissues(P<0.001). The overall survival(OS) time of patients with high KIF4 A expression was shorter than that of those with low KIF4 A expression(P=0.002), and the area under curve(AUC) of ROC curves for the 1-, 3-, and 5-year OS were 0.783, 0.662 and 0.574, respectively. The clinical stage(HR=2.084, 95% CI=1.590-2.733,P<0.001), T stage(HR=1.980, 95% CI=1.541-2.543,P<0.001) and KIF4 A expression level(HR=1.113, 95% CI=1.062-1.167,P<0.001) were significantly associated with OS, and high expression of KIF4 A(HR=1.089, 95% CI=1.034-1.147,P=0.001) was an independent risk factor for the prognosis of HCC patients. The nomogram results showed that KIF4 A expression had a significant effect on the total score, while other clinicopathologic factors had relatively little effect on the total score. Immunohistochemical detection confirmed that KIF4 A was positively expressed in HCC tissues, whereas it was weakly positively or negatively expressed in adjacent liver tissues. The results of GSEA enrichment analysis suggested that KIF4 A was possibly involved in the regulation of nine signaling pathways that included base excision repair, cell cycle, DNA replication, mismatch repair,m TOR signaling pathway, nucleotide excision repair, P53 signaling pathway, pathways in cancer, and phosphatidylinositol signaling system.Conclusion: KIF4 A is highly expressed in HCC tissue and significantly correlated with the clinical stage and histological grade as well as poor prognosis of HCC patients, suggesting that KIF4 A may be a potential molecular marker for prognostic prediction and targeted therapy for HCC patients.