Overexpression of GINS4 Is Associated With Tumor Progression and Poor Survival in Hepatocellular Carcinoma.

Ziying Zhang,Hui Xie,Peiguo Cao,Peng Chen

doi:10.3389/fonc.2021.654185

Abstract

PurposeOur research was aimed to identify the expression, clinical value and biological significance of GINS complex subunit 4 (GINS4) in hepatocellular carcinoma (HCC).Materials and MethodsGINS4 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 via 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.ResultsWGCNA 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.ConclusionGINS4 is overexpressed in HCC and is correlated with undesirable survival of HCC patients.

Highlights

Liver cancer is the second primary reason for tumor-associated deaths globally, with approximately 841,000 new diagnoses and 782,000 deaths annually [1]
weighted gene coexpression network analysis (WGCNA) confirmed that GINS complex subunit 4 (GINS4) was one of hub genes significantly associated with histological grade of hepatocellular carcinoma (HCC)
4,344 differently expressed genes (DEGs) in the The Cancer Genome Atlas (TCGA) database were applied for conducting gene co-expression network through WGCNA approach, estimating pivotal and candidate mRNAs that modulated histopathological grade in the progression of HCC [46]

Summary

Introduction

Liver cancer is the second primary reason for tumor-associated deaths globally, with approximately 841,000 new diagnoses and 782,000 deaths annually [1]. Liver cancer kills approximately 383,000 people per year in China, occupying about 51% of liver cancer-related deaths globally [2]. HCC, the primary subtype of liver cancer, accounts for 75–85% cases [3, 4]. The majority of cases are initially diagnosed at advanced HCC owing to the non-specific symptoms in early stage and the deficiency of sensitive diagnostic biomarkers, with a 5-year survival rate of lower than 20% [4, 10].

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