Overexpression of tousled-like kinase 2 predicts poor prognosis in HBV-related hepatocellular carcinoma patients after radical resection

Bang Liu; Ling-Ling Lu; Li Yu; Xuan Mei; Jia Liu; Jiao-Long Zheng; Xiao-Ling Zhou; Hai-Yan Lin; Xiu-Ling Zhu; Dong-Liang Li

doi:10.3389/fgene.2023.1326737

Overexpression of tousled-like kinase 2 predicts poor prognosis in HBV-related hepatocellular carcinoma patients after radical resection

Front Genet. 2024 Jan 26:14:1326737. doi: 10.3389/fgene.2023.1326737. eCollection 2023.

Authors

Bang Liu^#^{1

2}, Ling-Ling Lu^#³, Li Yu^#⁴, Xuan Mei¹, Jia Liu⁵, Jiao-Long Zheng², Xiao-Ling Zhou², Hai-Yan Lin², Xiu-Ling Zhu², Dong-Liang Li^{1

2}

Affiliations

¹ Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China.
² Department of Hepatobiliary Disease, 900th Hospital of Joint Logistics Support Force, Fuzhou, China.
³ Department of Infectious Disease, Fujian Medical University Union Hospital, Fuzhou, China.
⁴ Department of Digestive Diseases, 900th Hospital of Joint Logistics Support Force, Fuzhou, China.
⁵ Department of Hepatobiliary Surgery, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.

^# Contributed equally.

Abstract

Background: Tousled-like kinase 2 (TLK2) is integral to DNA repair, replication, and cell cycle regulation, crucial for maintaining genome stability and integrity. However, the expression and prognostic value of TLK2 in hepatitis B viral (HBV) -related hepatocellular carcinoma (HCC) remains unclear. Methods: We examined TLK2 expression and prognostic implications in pan-cancer by using diverse databases. Subsequently, TLK2 expression in HBV-related HCC tissues and adjacent tissues was assessed using quantitative real-time PCR and immunohistochemistry. The prognostic value of TLK2 was assessed through ROC curves, time-dependent ROC curves, Cox regression, Kaplan-Meier curve, and decision curve analysis. Additionally, analyses of immune infiltration, protein-protein interactions, key molecules of tumor-related signaling pathways, molecular subtypes, and TLK2-associated differentially expressed genes (DEGs) were conducted, along with GO/KEGG and GSEA enrichment analyses. Results: TLK2 expression was significantly higher in HCC tissues compared to adjacent tissues and correlated with gender, AFP levels, albumin-bilirubin (ALBI) grade, microvascular invasion (MVI), maximum tumor diameter, tumor number, and TNM stage. TLK2 overexpression emerged as an independent risk factor for overall survival (OS) and recurrence-free survival (RFS) in HBV-related HCC patients. An integrated OS nomogram model, incorporating TLK2, age, ALBI grade, MVI, and tumor number, displayed enhanced prognostic capability (C-index: 0.765, 95% CI: 0.732-0.798) in predicting OS and has a higher net benefit than the TNM stage. Moreover, TLK2 expression correlated closely with immune cell infiltration and key molecules of signaling pathways. Functional enrichment analyses highlighted significant associations with DNA duplex unwinding, double-strand break repair, DNA replication, cell cycle, E2F targets, G2M checkpoint, and MYC targets V1. Conclusion: TLK2 is notably overexpressed in HBV-related HCC and emerges as a promising prognostic biomarker, necessitating further validation.

Keywords: HBV-related HCC; Tlk2; enrichment analysis; immune infiltration; prognostic.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by Guiding Projects of Social Development of Fujian Province (Grant number: 2021Y0062), 900th Hospital of Joint Logistics Support Force Fund (Grant number: 2020Q02, 2021ZD04, and 2021JQ04), and Startup Fund for Scientific Research of Fujian Medical University (Grant number: 2020QH1249).