Role of DTL in Hepatocellular Carcinoma and Its Impact on the Tumor Microenvironment

Zuyin Li; Rangrang Wang; Chen Qiu; Can Cao; Jianming Zhang; Jun Ge; Yuanping Shi

doi:10.3389/fimmu.2022.834606

Role of DTL in Hepatocellular Carcinoma and Its Impact on the Tumor Microenvironment

Front Immunol. 2022 Mar 22:13:834606. doi: 10.3389/fimmu.2022.834606. eCollection 2022.

Authors

Zuyin Li^{1

2}, Rangrang Wang^{2

3}, Chen Qiu⁴, Can Cao², Jianming Zhang^{2

3}, Jun Ge⁵, Yuanping Shi⁶

Affiliations

¹ Department of Hepatobiliary Surgery, Peking University Organ Transplantation Institute, Peking University People's Hospital, Beijing, China.
² Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
⁴ Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, Shanghai, China.
⁵ Department of General Surgery, The 306th Hospital of People's Liberation Army (PLA)-Peking University Teaching Hospital, Beijing, China.
⁶ Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Background: The crucial role of DTL has been previously implicated in genomic stability; however, its prognostic value and its relation with tumor immunity in hepatocellular carcinoma (HCC) remain to be further explored.

Methods: Transcriptional and mutational datasets as well as clinical information were retrieved from the GEO, ICGC, and TCGA databases. Differentially expressed genes (DEGs) were obtained from the comparison of DTL^high and DTL^low expression groups of the TCGA-HCC cohort. Those genes were under KEGG and gene ontology (GO) analyses to decipher the influence of the DTL gene on the biological behavior of HCC tumor cells. The survival status and mutational characteristics of patients according to DTL levels were depicted and analyzed. The DTL overexpression in HCC and its impact on prognosis were further confirmed by a cohort of 114 HCC patients (validation cohort). The TIMER, GEPIA, and TISIDB databases were adopted to investigate the potential relations between DTL levels and the status of immune cells, as well as immune cell infiltrations.

Results: The DTL gene is overexpressed in tumor tissues compared with distant non-malignant liver tissues, and DTL overexpression in HCC would enhance the HCC cells in the activities of cell cycle and division. HCC patients with high DTL expression have unfavorable clinical outcomes and harbor more somatic mutations than those with low DTL expression, and multivariate analysis also revealed that DTL overexpression could act as an independent biomarker for prognosis. Moreover, the DTL gene was positively linked to marker sets of infiltrating activated CD8+ and CD4+ T cells; however, these cells demonstrated to be functionally exhausted.

Conclusions: Patients with a DTL overexpression phenotype in HCC have poorer prognosis than those in the DTL^low group due to the role of the DTL gene in the process of pro-cell proliferation, accompanied by the immunosuppressive microenvironment and T cell exhaustion.

Keywords: DNA replication; DTL; cell cycle; immune cell infiltration; prognosis.

MeSH terms

Biomarkers, Tumor / metabolism
Carcinoma, Hepatocellular* / pathology
Humans
Liver Neoplasms* / pathology
Nuclear Proteins* / genetics
Prognosis
Tumor Microenvironment*

Substances

Biomarkers, Tumor
DTL protein, human
Nuclear Proteins