Zhang Ziying, Chen Peng, Xie Hui, Cao Peiguo
Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China.
Department of Urology, Xiangya Hospital, Central South University, Changsha, China.
Front Oncol. 2021 Mar 25;11:654185. doi: 10.3389/fonc.2021.654185. eCollection 2021.
Our research was aimed to identify the expression, clinical value and biological significance of GINS complex subunit 4 (GINS4) in hepatocellular carcinoma (HCC).
GINS4 was initially screened through weighted gene co-expression network analysis (WGCNA). The TCGA, GEO, and TIMER databases were applied for analyzing the GINS4 mRNA expression in HCC. GINS4 protein levels were detected immunohistochemistry (IHC). Receiver operating characteristic (ROC) curve was applied for estimating the diagnostic significance of GINS4 in HCC. Kaplan-Meier plots, Cox model, and nomogram were used to assess the prognostic performance of GINS4 in HCC. Nomogram validation was conducted through time-dependent ROC and decision curve analysis (DCA). The Wanderer, UALCAN, and DiseaseMeth databases were utilized to identify GINS4 methylation levels in HCC. Genes co-expressed with GINS4 in HCC were estimated through the TCGA, cBioPortal, and GEPIA. GO, KEGG, and GSEA unraveled the possible biological mechanisms of GINS4 in HCC.
WGCNA confirmed that GINS4 was one of hub genes significantly associated with histological grade of HCC. Multiple databases confirmed the significant upregulation of GINS4 in HCC tissues compared with non-tumor controls. IHC analysis of 35 HCC patients demonstrated that overexpressed GINS4 positively correlated with advanced TNM stage and poor pathological differentiation. GINS4 could effectively differentiate HCC cases from healthy individuals, with an AUC of 0.865. Increased GINS4 expression predicted unsatisfactory prognosis in HCC patients, especially in age >60 years, histological grade 1, HBV infection-negative, and occurring relapse subgroup. Nomogram incorporating GINS4 level and TNM stage displayed satisfactory predictive accuracy and clinical utility in predicting HCC prognosis. Upregulated GINS4 exhibited hypomethylated levels in HCC. Functional analysis indicated that GINS4 potentially positively modulated cell cycle and PI3K/AKT/mTOR pathway.
GINS4 is overexpressed in HCC and is correlated with undesirable survival of HCC patients.
本研究旨在确定GINS复合体亚基4（GINS4）在肝细胞癌（HCC）中的表达、临床价值及生物学意义。
最初通过加权基因共表达网络分析（WGCNA）筛选出GINS4。应用TCGA、GEO和TIMER数据库分析HCC中GINS4 mRNA的表达。采用免疫组织化学（IHC）检测GINS4蛋白水平。应用受试者工作特征（ROC）曲线评估GINS4在HCC中的诊断意义。采用Kaplan-Meier曲线、Cox模型和列线图评估GINS4在HCC中的预后性能。通过时间依赖性ROC和决策曲线分析（DCA）进行列线图验证。利用Wanderer、UALCAN和DiseaseMeth数据库确定HCC中GINS4的甲基化水平。通过TCGA、cBioPortal和GEPIA评估HCC中与GINS4共表达的基因。GO、KEGG和GSEA揭示了GINS4在HCC中的可能生物学机制。
WGCNA证实GINS4是与HCC组织学分级显著相关的关键基因之一。多个数据库证实，与非肿瘤对照相比，HCC组织中GINS4显著上调。对35例HCC患者的IHC分析表明，GINS4过表达与晚期TNM分期和不良病理分化呈正相关。GINS4能够有效地区分HCC病例与健康个体，曲线下面积（AUC）为0.865。GINS4表达增加预示HCC患者预后不良，尤其是年龄＞60岁、组织学1级、HBV感染阴性及复发亚组。纳入GINS4水平和TNM分期的列线图在预测HCC预后方面显示出令人满意的预测准确性和临床实用性。上调的GINS4在HCC中表现出低甲基化水平。功能分析表明，GINS4可能正向调节细胞周期和PI3K/AKT/mTOR通路。
GINS4在HCC中过表达，与HCC患者不良生存相关。
