1. Department of Hepatobiliary Surgery, Peking University Organ Transplantation Institute, Peking University People's Hospital, Beijing, 100034, China.
2. Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China.
3. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.
4. Department of General Surgery, Huashan Hospital North, Fudan University, Shanghai 201907, China.
5. Institute of Gallstone Disease, Center of Gallbladder Disease, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
6. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 20040, China.
7. Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, 201700, China.
#Zuyin Li, Guohe Song and Dezhen Guo contributed equally to the work.
Background: GINS2 has been reported to have prognostic value in several solid tumors other than hepatocellular carcinoma (HCC), and its influence on tumor immunity has not been investigated thus far.
Methods: The transcriptome profiles were retrieved from two public databases, GEO and TCGA. The median GINS2 expression was considered as cutoff to define GINS2high and GINS2low groups and to obtain differentially expressed genes. These genes were then subjected to KEGG pathway and gene ontology (GO) analysis and to gene set enrichment analysis (GSEA). Survival analyses according to GINS2 level were performed utilizing Kaplan-Meier plotter. TIMER database was adopted to investigate associations between GINS2 level and infiltrating immunocytes, and the correlation between immunocyte-related gene expression and GINS2 level was evaluated via GEPIA database. A 236-patient validation cohort were applied to confirm the bioinformatic results of TCGA and TIMER database.
Results: GINS2 is augmented in tumorous tissues of HCC patients compared with nontumor specimens, and GINS2-overexpressed patients have poorer overall survival (OS) and disease-specific survival (DSS) than those with low GINS2 expression in HCC (P = 0.009 and P = 0.002 respectively). Cell cycle and DNA replication were two main processes that enriched in tumor cells overexpressed GINS2 gene (NES = 1.848, P = 0.007; and NES = 1.907, P = 0.005, respectively). Moreover, GINS2 correlates positively with markers of activated CD8+ and CD4+ T cells, as well as exhausted T lymphocytes.
Conclusions: HCC patients overexpressed GINS2 have poorer prognoses than those with low GINS2 expression, possibly as a result of the function of GINS2 in cell cycle and DNA replication as well the exhaustion of T lymphocytes.
Keywords: GINS2, DNA replication, cell cycle, immune cell infiltration.