Analysis of the expression and prognostic significance of dentideless E3 ubiquitin ligase in hepatocellular carcinoma based on bioinformatics methods

Abstract

Abstract: Objective:To investigate the expression and prognostic value of dentideless E3 ubiquitin ligase (DTL) in hepatocellular carcinoma (HCC).
Method:Transcriptome data of 374 HCC tissues and 50 paracancer tissues were downloaded from The Cancer Genome Atlas (TCGA) database. The GSE121248 dataset was downloaded from the Gene Expression Omnibus (GEO) database, and transcriptome data including 70 HCC tissues and 37 paracancer normal tissues was obtained. The expression level of DTL in HCC tissues was compared with that in normal adjacent tissues. Kaplan-meier method was used for survival analysis, and log-rank test was used to compare the overall survival rate and progression-free interval rate of HCC patients between the DTL high expression group and the DTL low expression group. The risk factors for poor prognosis of HCC patients were analyzed by Cox regression analysis. The receiver operator characteristic (ROC) curve of DTL expression level for HCC diagnosis was plotted. The effect of DTL on the prognosis of HCC patients was predicted by using multivariate Cox regression analysis. Meanwhile, GSEA enrichment analysis was performed for differentially expressed genes in HCC tissues of DTL high expression group and DTL low expression group.
Result:The expression level of DTL in HCC tissues was higher than that in adjacent normal tissues (P<0.001). There were statistically significant differences in age, race, AFP level, histologic grade, pathological stage and T stage between the DTL high expression group and the DTL low expression group (P<0.05). Kaplan-meier survival analysis showed that overall survival and progression-free survival were shorter in HCC patients with high DTL expression compared with HCC patients with low DTL expression (P=0.005, P<0.001). ROC curve showed that DTL expression level had strong diagnostic ability for HCC [area under the curve (AUC) was 0.96]. The c-index of DTL expression was 0.663 (95%CI 0.54~0.61). GSEA enrichment analysis showed that DTL may affect the occurrence and development of HCC through the influence of cell cycle, chromosome maintenance, DNA replication, G2/M checkpoint, mitotic stage, TP53 transcription regulation and other pathways.
Conclusion:High expression of DTL predicts poor prognosis of hepatocellular carcinoma, suggesting that DTL may be a potential biomarker for diagnosis and prognosis of hepatocellular carcinoma.

Key words: Dentideless E3 ubiquitin ligase, Hepatocellular carcinoma, Prognosis

Liu Zhenrong, Xiao Ting. Analysis of the expression and prognostic significance of dentideless E3 ubiquitin ligase in hepatocellular carcinoma based on bioinformatics methods[J]. Electronic Journal of Liver Tumor, 2022, 9(1): 41-47.

References

[1] SIEGEL R L, MILLER K D, JEMAL A.Cancer statistics, 2020[J]. CA Cancer J Clin, 2020, 70(1): 7-30.
[2] VILLANUEVA A.Hepatocellular Carcinoma[J]. N Engl J Med, 2019, 380(15): 1450-1462.
[3] SARTORIUS K, SARTORIUS B, ALDOUS C, et al.Global and country underestimation of hepatocellular carcinoma (HCC) in 2012 and its implications[J]. Cancer Epidemiol, 2015, 39(3): 284-290.
[4] CHEN W, ZHENG R, BAADE P D, et al.Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132.
[5] ARAVALLI R N, STEER C J.Immune-Mediated Therapies for Liver Cancer[J]. Genes (Basel), 2017, 8(2): 76.
[6] DE LOPE C R, TREMOSINI S, FORNER A, et al. Management of HCC[J]. J Hepatol, 2012, 56 Suppl 1: S75-S87.
[7] LLOVET J M, ZUCMAN-ROSSI J, PIKARSKY E, et al.Hepatocellular carcinoma[J]. Nat Rev Dis Primers, 2016, 2: 16018.
[8] VANDEMARK A P, HILL C P.Structural basis of ubiquitylation[J]. Curr Opin Struct Biol, 2002, 12(6): 822-830.
[9] SLENN T J, MORRIS B, HAVENS C G, et al.Thymine DNA glycosylase is a CRL4Cdt2 substrate[J]. J Biol Chem, 2014, 289(33): 23043-23055.
[10] CHEN Y C, CHEN I S, HUANG G J, et al.Targeting DTL induces cell cycle arrest and senescence and suppresses cell growth and colony formation through TPX2 inhibition in human hepatocellular carcinoma cells[J]. Onco Targets Ther, 2018, 11: 1601-1616.
[11] LI T, FAN J, WANG B, et al.TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells[J]. Cancer Res, 2017, 77(21): e108-e110.
[12] TAKEUCHI T, TOMIDA S, YATABE Y, et al.Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors[J]. J Clin Oncol, 2006, 24(11): 1679-1688.
[13] BRAY F, FERLAY J, SOERJOMATARAM I, et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424.
[14] POPOVIC D, VUCIC D, DIKIC I.Ubiquitination in disease pathogenesis and treatment[J]. Nat Med, 2014, 20(11): 1242-1253.
[15] GRUMATI P, DIKIC I.Ubiquitin signaling and autophagy[J]. J Biol Chem, 2018, 293(15): 5404-5413.
[16] CHEUNG W M, CHU A H, CHU P W, et al.Cloning and expression of a novel nuclear matrix-associated protein that is regulated during the retinoic acid-induced neuronal differentiation[J]. J Biol Chem, 2001, 276(20): 17083-17091.
[17] TONG X, ZHANG D, GUHA A, et al.CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting Ubiquitination-Dependent Degradation of the Mammalian CRY1[J]. PLoS One, 2015, 10(10): e0139725.
[18] ABBAS T, DUTTA A.CRL4Cdt2: master coordinator of cell cycle progression and genome stability[J]. Cell Cycle, 2011, 10(2): 241-249.
[19] ROSSI M, DUAN S, JEONG Y T, et al.Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase[J]. Mol Cell, 2013, 49(6): 1159-1166.
[20] PEREZ-PEñA J, CORRALES-SáNCHEZ V, AMIR E, et al. Ubiquitin-conjugating enzyme E2T (UBE2T) and denticleless protein homolog (DTL) are linked to poor outcome in breast and lung cancers[J]. Sci Rep, 2017, 7(1): 17530.
[21] UEKI T, NISHIDATE T, PARK J H, et al.Involvement of elevated expression of multiple cell-cycle regulator, DTL/RAMP (denticleless/RA-regulated nuclear matrix associated protein), in the growth of breast cancer cells[J]. Oncogene, 2008, 27(43): 5672-5683.
[22] CUI H, WANG Q, LEI Z, et al.DTL promotes cancer progression by PDCD4 ubiquitin-dependent degradation[J]. J Exp Clin Cancer Res, 2019, 38(1): 350.