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

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Apr 8

PMID 35392073

Authors

Zuyin Li

Rangrang Wang

Chen Qiu

Can Cao

Jianming Zhang

Jun Ge

Yuanping Shi

Affiliations

Soon will be listed here.

Abstract

Background: The crucial role of 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 and DTL 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 gene is overexpressed in tumor tissues compared with distant non-malignant liver tissues, and overexpression in HCC would enhance the HCC cells in the activities of cell cycle and division. HCC patients with high expression have unfavorable clinical outcomes and harbor more somatic mutations than those with low DTL expression, and multivariate analysis also revealed that overexpression could act as an independent biomarker for prognosis. Moreover, the 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 overexpression phenotype in HCC have poorer prognosis than those in the DTL group due to the role of the gene in the process of pro-cell proliferation, accompanied by the immunosuppressive microenvironment and T cell exhaustion.

Citing Articles

Identification of Crucial Cancer Stem Cell Genes Linked to Immune Cell Infiltration and Survival in Hepatocellular Carcinoma.

Huang L, Wu S, Liu Y, Liu H, Chien P, Lin H Int J Mol Sci. 2024; 25(22).

PMID: 39596041 PMC: 11593742. DOI: 10.3390/ijms252211969.

Evaluation of Genes and Molecular Pathways Involved in Pathogenesis of Sickle Cell Anemia: A Bioinformatics Analysis and Future Perspective.

Maddah R, Etemad S, Amiri B, Ghaderi H, Zarei H, Faghihkhorasani F Iran J Public Health. 2024; 53(6):1404-1415.

PMID: 39430157 PMC: 11488559.

Hypoxia-induced DTL promotes the proliferation, metastasis, and sorafenib resistance of hepatocellular carcinoma through ubiquitin-mediated degradation of SLTM and subsequent Notch pathway activation.

Chen Z, Mu M, Yang G, Qi H, Fu X, Wang G Cell Death Dis. 2024; 15(10):734.

PMID: 39384740 PMC: 11464529. DOI: 10.1038/s41419-024-07089-4.

Enhanced anticancer activity of silver doped zinc oxide magnetic nanocarrier loaded with sorafenib for hepatocellular carcinoma treatment.

Khafaga D, Eid M, Mohamed M, Abdelmaksoud M, Afify M, El-Khawaga A Sci Rep. 2024; 14(1):15538.

PMID: 38969729 PMC: 11226637. DOI: 10.1038/s41598-024-65235-6.

Pan-cancer analysis and experimental validation of DTL as a potential diagnosis, prognosis and immunotherapy biomarker.

Tang Y, Lei Y, Gao P, Jia J, Du H, Wang Q BMC Cancer. 2023; 23(1):328.

PMID: 37038185 PMC: 10088150. DOI: 10.1186/s12885-023-10755-z.

References

Jin J, Arias E, Chen J, Harper J, Walter J . A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell. 2006; 23(5):709-21. DOI: 10.1016/j.molcel.2006.08.010. View

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J . TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21):e108-e110. PMC: 6042652. DOI: 10.1158/0008-5472.CAN-17-0307. View

Pan J, Zhou H, Cooper L, Huang J, Zhu S, Zhao X . LAYN Is a Prognostic Biomarker and Correlated With Immune Infiltrates in Gastric and Colon Cancers. Front Immunol. 2019; 10:6. PMC: 6362421. DOI: 10.3389/fimmu.2019.00006. View

Facciabene A, Motz G, Coukos G . T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res. 2012; 72(9):2162-71. PMC: 3342842. DOI: 10.1158/0008-5472.CAN-11-3687. View

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

Panagopoulos A, Taraviras S, Nishitani H, Lygerou Z . CRL4: Coupling Genome Stability to Ubiquitination. Trends Cell Biol. 2020; 30(4):290-302. DOI: 10.1016/j.tcb.2020.01.005. View

Abbas T, Dutta A . CRL4Cdt2: master coordinator of cell cycle progression and genome stability. Cell Cycle. 2011; 10(2):241-9. PMC: 3025761. DOI: 10.4161/cc.10.2.14530. View

Benamar M, Guessous F, Du K, Corbett P, Obeid J, Gioeli D . Inactivation of the CRL4-CDT2-SET8/p21 ubiquitylation and degradation axis underlies the therapeutic efficacy of pevonedistat in melanoma. EBioMedicine. 2016; 10:85-100. PMC: 5006603. DOI: 10.1016/j.ebiom.2016.06.023. View

Evans D, Zhang H, Ham H, Pei H, Lee S, Kim J . MMSET is dynamically regulated during cell-cycle progression and promotes normal DNA replication. Cell Cycle. 2016; 15(1):95-105. PMC: 4825781. DOI: 10.1080/15384101.2015.1121323. View

10.

Li B, Severson E, Pignon J, Zhao H, Li T, Novak J . Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016; 17(1):174. PMC: 4993001. DOI: 10.1186/s13059-016-1028-7. View

11.

Terai K, Abbas T, Jazaeri A, Dutta A . CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis. Mol Cell. 2010; 37(1):143-9. PMC: 2818832. DOI: 10.1016/j.molcel.2009.12.018. View

12.

Kim Y, Starostina N, Kipreos E . The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing. Genes Dev. 2008; 22(18):2507-19. PMC: 2546690. DOI: 10.1101/gad.1703708. View

13.

Llovet J, Kelley R, Villanueva A, Singal A, Pikarsky E, Roayaie S . Hepatocellular carcinoma. Nat Rev Dis Primers. 2021; 7(1):6. DOI: 10.1038/s41572-020-00240-3. View

14.

Su C, Jia S, Liu H . Immunolocalization of CD163+ Tumor-Associated Macrophages and Symmetric Proliferation of Ki-67 as Biomarkers to Differentiate New Different Grades of Laryngeal Dysplasia. Am J Clin Pathol. 2017; 149(1):8-16. DOI: 10.1093/ajcp/aqx107. View

15.

Beck D, Burton A, Oda H, Ziegler-Birling C, Torres-Padilla M, Reinberg D . The role of PR-Set7 in replication licensing depends on Suv4-20h. Genes Dev. 2012; 26(23):2580-9. PMC: 3521623. DOI: 10.1101/gad.195636.112. View

16.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

17.

Mackintosh C, Ordonez J, Garcia-Dominguez D, Sevillano V, Llombart-Bosch A, Szuhai K . 1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma. Oncogene. 2011; 31(10):1287-98. DOI: 10.1038/onc.2011.317. View

18.

Kiran S, Dar A, Singh S, Lee K, Dutta A . The Deubiquitinase USP46 Is Essential for Proliferation and Tumor Growth of HPV-Transformed Cancers. Mol Cell. 2018; 72(5):823-835.e5. PMC: 6294304. DOI: 10.1016/j.molcel.2018.09.019. View

19.

Jia Q, Wu W, Wang Y, Alexander P, Sun C, Gong Z . Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer. Nat Commun. 2018; 9(1):5361. PMC: 6299138. DOI: 10.1038/s41467-018-07767-w. View

20.

Song W, Mazzieri R, Yang T, Gobe G . Translational Significance for Tumor Metastasis of Tumor-Associated Macrophages and Epithelial-Mesenchymal Transition. Front Immunol. 2017; 8:1106. PMC: 5601389. DOI: 10.3389/fimmu.2017.01106. View