Neuroblastoma Patient Outcomes, Tumor Differentiation, and ERK Activation Are Correlated with Expression Levels of the Ubiquitin Ligase UBE4B

Overview

Journal Genes Cancer

Specialty Oncology

Date 2016 Mar 26

PMID 27014418

Citations 10

Authors

Sarah E Woodfield

Rong Jun Guo

Yin Liu

Angela M Major

Emporia Faith Hollingsworth

Sandra Indiviglio

Sarah B Whittle

Qianxing Mo

Andrew J Bean

Michael Ittmann

Dolores Lopez-Terrada

Peter E Zage

Affiliations

Soon will be listed here.

Abstract

Background: UBE4B is an E3/E4 ubiquitin ligase whose gene is located in chromosome 1p36.22. We analyzed the associations of UBE4B gene and protein expression with neuroblastoma patient outcomes and with tumor prognostic features and histology.

Methods: We evaluated the association of UBE4B gene expression with neuroblastoma patient outcomes using the R2 Platform. We screened neuroblastoma tumor samples for UBE4B protein expression using immunohistochemistry. FISH for UBE4B and 1p36 deletion was performed on tumor samples. We then evaluated UBE4B expression for associations with prognostic factors and with levels of phosphorylated ERK in neuroblastoma tumors and cell lines.

Results: Low UBE4B gene expression is associated with poor outcomes in patients with neuroblastoma and with worse outcomes in all patient subgroups. UBE4B protein expression was associated with neuroblastoma tumor differentiation, and decreased UBE4B protein levels were associated with high-risk features. UBE4B protein levels were also associated with levels of phosphorylated ERK.

Conclusions: We have demonstrated associations between UBE4B gene expression and neuroblastoma patient outcomes and prognostic features. Reduced UBE4B protein expression in neuroblastoma tumors was associated with high-risk features, a lack of differentiation, and with ERK activation. These results suggest UBE4B may contribute to the poor prognosis of neuroblastoma tumors with 1p36 deletions and that UBE4B expression may mediate neuroblastoma differentiation.

Citing Articles

UBE4B interacts with the ITCH E3 ubiquitin ligase to induce Ku70 and c-FLIPL polyubiquitination and enhanced neuroblastoma apoptosis.

Le Clorennec C, Subramonian D, Huo Y, Zage P Cell Death Dis. 2023; 14(11):739.

PMID: 37957138 PMC: 10643674. DOI: 10.1038/s41419-023-06252-7.

Ouabain Induces Transcript Changes and Activation of RhoA/ROCK Signaling in Cultured Epithelial Cells (MDCK).

Martinez-Rendon J, Hinojosa L, Xoconostle-Cazares B, Ramirez-Pool J, Castillo A, Cereijido M Curr Issues Mol Biol. 2023; 45(9):7538-7556.

PMID: 37754259 PMC: 10528288. DOI: 10.3390/cimb45090475.

Targeting the RET tyrosine kinase in neuroblastoma: A review and application of a novel selective drug design strategy.

Steen E, Basilaia M, Kim W, Getz T, Gustafson J, Zage P Biochem Pharmacol. 2023; 216:115751.

PMID: 37595672 PMC: 10911250. DOI: 10.1016/j.bcp.2023.115751.

Identification of a novel gene signature for neuroblastoma differentiation using a Boolean implication network.

Zage P, Huo Y, Subramonian D, Le Clorennec C, Ghosh P, Sahoo D Genes Chromosomes Cancer. 2023; 62(6):313-331.

PMID: 36680522 PMC: 10257350. DOI: 10.1002/gcc.23124.

Upregulated UBE4B expression correlates with poor prognosis and tumor immune infiltration in hepatocellular carcinoma.

Shao X, Zhu J, Shi Y, Fang H, Chen J, Zhang Y Aging (Albany NY). 2022; 14(23):9632-9646.

PMID: 36470669 PMC: 9792214. DOI: 10.18632/aging.204414.

References

Schlesinger H, Gerson J, Moorhead P, Maguire H, Hummeler K . Establishment and characterization of human neuroblastoma cell lines. Cancer Res. 1976; 36(9 pt.1):3094-100. View

Shimada H, Ambros I, Dehner L, Hata J, JOSHI V, Roald B . The International Neuroblastoma Pathology Classification (the Shimada system). Cancer. 1999; 86(2):364-72. View

Hatakeyama S, Yada M, Matsumoto M, Ishida N, Nakayama K . U box proteins as a new family of ubiquitin-protein ligases. J Biol Chem. 2001; 276(35):33111-20. DOI: 10.1074/jbc.M102755200. View

Maris J, Guo C, Blake D, White P, Hogarty M, Thompson P . Comprehensive analysis of chromosome 1p deletions in neuroblastoma. Med Pediatr Oncol. 2001; 36(1):32-6. DOI: 10.1002/1096-911X(20010101)36:1<32::AID-MPO1009>3.0.CO;2-0. View

Krona C, Ejeskar K, Abel F, Kogner P, Bjelke J, Bjork E . Screening for gene mutations in a 500 kb neuroblastoma tumor suppressor candidate region in chromosome 1p; mutation and stage-specific expression in UBE4B/UFD2. Oncogene. 2003; 22(15):2343-51. DOI: 10.1038/sj.onc.1206324. View

Lau L, Tai D, Weitzman S, Grant R, Baruchel S, Malkin D . Factors influencing survival in children with recurrent neuroblastoma. J Pediatr Hematol Oncol. 2004; 26(4):227-32. DOI: 10.1097/00043426-200404000-00003. View

Kwabi-Addo B, Wang J, Erdem H, Vaid A, Castro P, Ayala G . The expression of Sprouty1, an inhibitor of fibroblast growth factor signal transduction, is decreased in human prostate cancer. Cancer Res. 2004; 64(14):4728-35. DOI: 10.1158/0008-5472.CAN-03-3759. View

Caren H, Ejeskar K, Fransson S, Hesson L, Latif F, Sjoberg R . A cluster of genes located in 1p36 are down-regulated in neuroblastomas with poor prognosis, but not due to CpG island methylation. Mol Cancer. 2005; 4(1):10. PMC: 554762. DOI: 10.1186/1476-4598-4-10. View

Attiyeh E, London W, Mosse Y, Wang Q, Winter C, Khazi D . Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med. 2005; 353(21):2243-53. DOI: 10.1056/NEJMoa052399. View

10.

Henrich K, Fischer M, Mertens D, Benner A, Wiedemeyer R, Brors B . Reduced expression of CAMTA1 correlates with adverse outcome in neuroblastoma patients. Clin Cancer Res. 2006; 12(1):131-8. DOI: 10.1158/1078-0432.CCR-05-1431. View

11.

Spitz R, Hero B, Simon T, Berthold F . Loss in chromosome 11q identifies tumors with increased risk for metastatic relapses in localized and 4S neuroblastoma. Clin Cancer Res. 2006; 12(11 Pt 1):3368-73. DOI: 10.1158/1078-0432.CCR-05-2495. View

12.

Oppenheimer O, Cheung N, Gerald W . The RET oncogene is a critical component of transcriptional programs associated with retinoic acid-induced differentiation in neuroblastoma. Mol Cancer Ther. 2007; 6(4):1300-9. DOI: 10.1158/1535-7163.MCT-06-0587. View

13.

Schlisio S, Kenchappa R, Vredeveld L, George R, Stewart R, Greulich H . The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 2008; 22(7):884-93. PMC: 2279200. DOI: 10.1101/gad.1648608. View

14.

Cole K, Attiyeh E, Mosse Y, LaQuaglia M, Diskin S, Brodeur G . A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Mol Cancer Res. 2008; 6(5):735-42. PMC: 3760152. DOI: 10.1158/1541-7786.MCR-07-2102. View

15.

Fujita T, Igarashi J, Okawa E, Gotoh T, Manne J, Kolla V . CHD5, a tumor suppressor gene deleted from 1p36.31 in neuroblastomas. J Natl Cancer Inst. 2008; 100(13):940-9. PMC: 2483574. DOI: 10.1093/jnci/djn176. View

16.

Munirajan A, Ando K, Mukai A, Takahashi M, Suenaga Y, Ohira M . KIF1Bbeta functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36.2 by inducing apoptotic cell death. J Biol Chem. 2008; 283(36):24426-34. PMC: 3259808. DOI: 10.1074/jbc.M802316200. View

17.

Lavarino C, Cheung N, Garcia I, Domenech G, de Torres C, Alaminos M . Specific gene expression profiles and chromosomal abnormalities are associated with infant disseminated neuroblastoma. BMC Cancer. 2009; 9:44. PMC: 2642835. DOI: 10.1186/1471-2407-9-44. View

18.

Trapnell C, Pachter L, Salzberg S . TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009; 25(9):1105-11. PMC: 2672628. DOI: 10.1093/bioinformatics/btp120. View

19.

Huang S, Laoukili J, Epping M, Koster J, Holzel M, Westerman B . ZNF423 is critically required for retinoic acid-induced differentiation and is a marker of neuroblastoma outcome. Cancer Cell. 2009; 15(4):328-40. PMC: 2693316. DOI: 10.1016/j.ccr.2009.02.023. View

20.

Robinson M, McCarthy D, Smyth G . edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2009; 26(1):139-40. PMC: 2796818. DOI: 10.1093/bioinformatics/btp616. View