Expressional and functional characteristics of checkpoint kinase 1 as a prognostic biomarker in hepatocellular carcinoma

Encheng Bai; Mingwei Dong; Xiahui Lin; Dalong Sun; Ling Dong

doi:10.21037/tcr-22-1701

Expressional and functional characteristics of checkpoint kinase 1 as a prognostic biomarker in hepatocellular carcinoma

Transl Cancer Res. 2022 Dec;11(12):4272-4288. doi: 10.21037/tcr-22-1701.

Authors

Encheng Bai^#^{1

2}, Mingwei Dong^#^{1

2}, Xiahui Lin^#¹, Dalong Sun^{1

2

3}, Ling Dong^{1

3}

Affiliations

¹ Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
² Department of Gastroenterology and Hepatology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China.
³ Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, China.

^# Contributed equally.

Abstract

Background: Hepatocellular carcinoma (HCC) is the most common pathological subtype of liver cancer and is the third leading cause of cancer death worldwide. Checkpoint kinase 1 (CHEK1), an essential serine/threonine kinase that regulates the cell cycle, is reported to be associated with carcinogenesis. However, the biological role and clinical significance of CHEK1 in HCC are still incompletely known.

Methods: In this research, CHEK1 messenger RNA (mRNA) levels in various liver hepatocellular carcinoma (LIHC) cohorts from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were evaluated. The Kaplan-Meier database was applied to identify the correlation between survival time and CHEK1 expression in patients with HCC. Gene set enrichment analysis (GSEA) was performed to explore the potential mechanism of CHEK1 in HCC, and NetworkAnalyst v. 3.0 (https://www.networkanalyst.ca/) was used to construct the regulatory networks of CHEK1 in HCC. Discriminant Regulon Expression Analysis (DoRothEA) was used to detect the activity of transcriptional factors (TFs) in gene-enriched cells (EC) with CHEK1 coexpression. In vitro experiments were conducted to investigate the effects of CHEK1 on the biological function of HCC cells.

Results: The CHEK1 mRNA level was overexpressed in HCC, and increased CHEK1 expression correlated with poor survival outcomes. The homo sapiens-microRNA-195 (hsa-miR-195) may have contributed to the upregulation of CHEK1 in HCC. GSEA and NetworkAnalyst v. 3.0 showed that CHEK1 played a crucial part in tumor proliferation of HCC and may be regulated by TF E2F1. DoRothEA showed increased transcriptional activity of E2F1 in gene-EC with CHEK1 coexpression. Moreover, experiments of cell function showed that the knockdown of CHEK1 weakened the aggressive behavior and proliferation of HCC cells. Overexpression of E2F1 increased the proliferation and invasion of HCC cells in vitro, while the silencing of CHEK1 dampened cell invasion induced by E2F1 overexpression.

Conclusions: These results identified the prognostic significance and expression characteristics of CHEK1 in HCC through bioinformatics analysis and experimental verification. This lays the foundation for further research on the diagnosis and treatment of HCC.

Keywords: Checkpoint kinase 1 (CHEK1); hepatocellular carcinoma (HCC); prognostic analysis; single-cell RNA sequence.