High Level of Ubiquitin Conjugate Enzyme E2O Indicates Poor Prognosis of Patients with Hepatocellular Carcinoma

Abstract

Objective

Ubiquitin conjugate enzyme E2O (UBE2O) is a ubiquitin-conjugating enzyme that has been reported to be involved in tumorigenesis. This study investigated the role of UBE2O in hepatocellular carcinoma (HCC).

Methods

The expression of UBE2O was detected using qRT-PCR, Western blotting, and immunohistochemical staining. Cell proliferation and Transwell assays were used to detect proliferation, migration, and invasion of HCC cells, respectively. Bioinformatic analysis was performed to analyze the relationship between UBE2O and the clinical features, prognosis, and immune cell infiltration of HCC.

Results

UBE2O was significantly over-expressed in HCC tissues. High expression of UBE2O was associated with poor tumor grade and poor prognosis. Functional experiments showed that down-regulation of UBE2O inhibited HCC cell proliferation, migration, and invasion. Co-expression gene analysis and gene set enrichment analysis showed that UBE2O was associated with protein hydrolysis, cell cycle, and cancer-related pathways in HCC. The results of immune analysis revealed that the expression of UBE2O was positively correlated with the immune infiltration and expression of immune-related chemokines of HCC.

Conclusions

UBE2O is significantly correlated with the prognosis of HCC and may be a valuable prognostic biomarker for HCC.

Keywords

ubiquitin conjugate enzyme E2O / hepatocellular carcinoma / prognosis / immune

References

[1] FornerA, ReigM, BruixJ. Hepatocellular carcinoma. Lancet, 2018, 391(10127): 1301-1314

[2] PinterM, Peck-radosavljevicM. Review article: systemic treatment of hepatocellular carcinoma. Aliment Pharmacol Ther, 2018, 48(6): 598-609

[3] YangJD, HainautP, GoresGJ, et al.. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol, 2019, 16(10): 589-604

[4] AltekruseSF, HenleySJ, CucinelliJE, et al.. Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States. Am J Gastroenterol, 2014, 109(4): 542-553

[5] ZhangG, LiR, DengY, et al.. Conditional survival of patients with hepatocellular carcinoma: results from the Surveillance, Epidemiology, and End Results registry. Expert Rev Gastroenterol Hepatol, 2018, 12(5): 515-523

[6] YokotaT, NagaiH, HaradaH, et al.. Identification, tissue expression, and chromosomal position of a novel gene encoding human ubiquitin-conjugating enzyme E2-230k. Gene, 2001, 267(1): 95-100

[7] Hormaechea-AgullaD, KimY, SongM S, et al.. New Insights into the Role of E2s in the Pathogenesis of Diseases: Lessons Learned from UBE2O. Mol Cells, 2018, 41(3): 168-178

[8] LinM, SmithLT, SmiragliaDJ, et al.. DNA copy number gains in head and neck squamous cell carcinoma. Oncogene, 2006, 25(9): 1424-1433

[9] ToffoliS, BarI, Abdel-SaterF, et al.. Identification by array comparative genomic hybridization of a new amplicon on chromosome 17q highly recurrent in BRCA1 mutated triple negative breast cancer. Breast Cancer Res, 2014, 16(6): 466

[10] VilaIK, YaoY, KimG, et al.. A UBE2O-AMPKalpha2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy. Cancer Cell, 2017, 31(2): 208-224

[11] ChenX, ZhangS, LiuC, et al.. UBE2O Promotes Progression and Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma. Onco Targets Ther, 2020, 13: 6191-6202

[12] LiuX, MaF, LiuC, et al.. UBE2O promotes the proliferation, EMT and stemness properties of breast cancer cells through the UBE2O/AMPKalpha2/mTORC1-MYC positive feedback loop. Cell Death Dis, 2020, 11(1): 10

[13] HuangY, YangX, LuY, et al.. UBE2O targets Mxi1 for ubiquitination and degradation to promote lung cancer progression and radioresistance. Cell Death Differ, 2021, 28(2): 671-684

[14] ClineMS, CraftB, SwatloskiT, et al.. Exploring TCGA Pan-Cancer data at the UCSC Cancer Genomics Browser. Sci Rep, 2013, 3: 2652

[15] LiT, FanJ, WangB, et al.. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res, 2017, 77(21): e108-e110

[16] LianQ, WangS, ZhangG, et al.. HCCDB: A Database of Hepatocellular Carcinoma Expression Atlas. Genomics Proteomics Bioinformatics, 2018, 16(4): 269-275

[17] VasaikarSV, StraubP, WangJ, et al.. LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res, 2018, 46(D1): D956-D963

[18] RuB, WongCN, TongY, et al.. TISIDB: an integrated repository portal for tumor-immune system interactions. Bioinformatics, 2019, 35(20): 4200-4202

[19] BrayF, FerlayJ, SoerjomataramI, et al.. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424

[20] HuangA, YangXR, ChungWY, et al.. Targeted therapy for hepatocellular carcinoma. Signal Transduct Target Ther, 2020, 5(1): 146

[21] ZhangX, ZhangJ, BauerA, et al.. Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated monoubiquitination of SMAD6. EMBO J, 2013, 32(7): 996-1007

[22] HaoYH, DoyleJM, RamanathanS, et al.. Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination. Cell, 2013, 152(5): 1051-1064

[23] ZhangX, ZhangJ, ZhangL, et al.. UBE2O negatively regulates TRAF6-mediated NF-kappaB activation by inhibiting TRAF6 polyubiquitination. Cell Res, 2013, 23(3): 366-377

[24] ChewV, LaiL, PanL, et al.. Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses. Proc Natl Acad Sci USA, 2017, 114(29): E5900-E5909

[25] LocyH, de MeyS, de MeyW, et al.. Immunomodulation of the Tumor Microenvironment: Turn Foe Into Friend. Front Immunol, 2018, 9: 2909

[26] GaoQ, QiuSJ, FanJ, et al.. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol, 2007, 25(18): 2586-2593

[27] ZhouG, SprengersD, BoorPPC, et al.. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas. Gastroenterology, 2017, 153(4): 1107-1119

[28] ZhuM, XuW, WeiC, et al.. CCL14 serves as a novel prognostic factor and tumor suppressor of HCC by modulating cell cycle and promoting apoptosis. Cell Death Dis, 2019, 10(11): 796

[29] SalemA, AlotaibiM, MrouehR, et al.. CCR7 as a therapeutic target in Cancer. Biochim Biophys Acta Rev Cancer, 2021, 1875(1): 188499

[30] LinT, LinZ, MaiP, et al.. Identification of prognostic biomarkers associated with the occurrence of portal vein tumor thrombus in hepatocellular carcinoma. Aging (Albany NY), 2021, 13(8): 11786-11807

[31] WangW, HuangP, ZhangL, et al.. Antitumor efficacy of C-X-C motif chemokine ligand 14 in hepatocellular carcinoma in vitro and in vivo. Cancer Sci, 2013, 104(11): 1523-1531