Evaluation of the Association of RHOB Expression with Molecular Risk Classes and Prognosis in Neuroblastoma

Year 2024, , 449 - 455, 12.01.2025

Burçin Baran , Gamze Sanlav , Selen Kum Özşengezer , Deniz Kızmazoğlu , Safiye Aktaş , Zekiye Altun , Nur Olgun

https://doi.org/10.32708/uutfd.1483064

Abstract

Neuroblastoma is the most common solid tumor of childhood originating from the developing nervous system. It shows a heterogeneous behavior with a clinical course ranging from localized or spontaneously regressive disease to metastatic disease resistant to intensive and multimodal treatment regimens. Ras Homolog Family Member B (RhoB) is a member of the Rho GTPase family and plays a role in cytoskeleton organization, receptor and signaling protein transmission, DNA damage repair and apoptosis. RhoB expression has been studied in different adult cancer types and has been found to be associated with good or poor prognosis in different cancer types. However, RhoB expression has not been studied as a candidate prognostic biomarker in pediatric cancers before. In our study, RhoB protein expression was examined in neuroblastoma patients by immunohistochemical methods. Overall survival and event-free survival of neuroblastoma patients in low, intermediate and high-risk groups were compared with RhoB expression and clinicopathological features of patients were examined with Spearman's correlation analysis. Although the number of patients in our study was small, our study revealed that RhoB expression may be a good prognostic biomarker for NB patients.

Keywords

Neuroblastoma, Pediatric cancers, Biomarker, Survival, Prognostic factor

Project Number

(TUBITAK) 2214-A programı (2018/2, 1059B141801571), Dokuz Eylül Üniversitesi BAP (İzmir, Türkiye) (2021. KB.SAG.044).

RHOB Ekspresyonun Nöroblastomda Moleküler Risk Sınıfları ve Prognoz ile İlişkisinin Değerlendirilmesi

Abstract

Nöroblastom, gelişmekte olan sinir sisteminden köken alan ve çocukluk çağının en sık görülen solid tümörüdür. Klinik seyri lokalize veya spontane gerileme gösterebilen hastalıktan, yoğun ve multimodal tedavi rejimlerine dirençli metastatik hastalığa değişen heterojen bir davranış göstermektedir. Ras Homolog Ailesi Üyesi B (RhoB), Rho GTPaz ailesinin bir üyesidir ve sitoiskeletet organizasyonunda, reseptör ve sinyal proteinlerinin iletiminde, DNA hasar tamirinde ve apoptozda rol oynar. RhoB ekspresyonu farklı erişkin kanser türlerinde incelenmiş ve farklı kanser türlerinde iyi veya kötü prognozla ilişkili olduğu saptanmıştır. Ne var ki, RhoB ekspresyonu aday bir prognostik biyobelirteç olarak pediatrik kanserlerde daha önce çalışılmamıştır. Yapılan çalışmamızda, RhoB protein ekspresyonu nöroblastom hastalarında immün histokimyasal boyama yöntemiyle incelenmiştir. RhoB ekspresyonu ile düşük, orta ve yüksek risk gruplarındaki nöroblastom hastalarının genel sağ kalımı ve olaysız sağ kalımları karşılaştırılmış ve RhoB ekspresyonu ile hastaların klinikopatolojik özellikleri Spearman’s korelasyon analizi ile incelenmiştir. Her ne kadar çalışmamızdaki hasta örneklem sayısı az olsa da çalışmamızda RhoB ekspresyonunun NB hastaları için iyi prognostik bir biyobelirteç olabileceği ortaya konmuştur.

Keywords

Nöroblastom, Çocukluk çağı kanserleri, Biyobelirteç, Sağ kalım, Prognostik faktör

Ethical Statement

Çalışma için Dokuz Eylül Üniversitesi Girişimsel Olmayan Etik Kurulu tarafından 27.04.2022 tarih ve 2022/16-03 nolu kararı ile etik kurul onayı alınmıştır.

Supporting Institution

Dokuz Eylül Üniversitesi, TUBİTAK

Project Number

(TUBITAK) 2214-A programı (2018/2, 1059B141801571), Dokuz Eylül Üniversitesi BAP (İzmir, Türkiye) (2021. KB.SAG.044).

Thanks

Türk Pediatrik Onkoloji Derneği (TPOG)'ne katkılarından dolayı teşekkür ederiz.

References

• 1.Shawraba F, Hammoud H, Mrad Y et al. Biomarkers in Neuroblastoma: An Insight into Their Potential Diagnostic and Prognostic Utilities. Curr Treat Options Oncol. 2021; 27;22(11):102.
• 2.Qiu B, Matthay KK. Advancing therapy for neuroblastoma. Nat Rev Clin Oncol. 2022; 19(8):515-533.
• 3.Irwin MS, Naranjo A, Zhang FF et al. Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group. J Clin Oncol. 2021; 10;39(29):3229-3241.
• 4.Cohn SL, Pearson AD, London WB et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009;10;27(2):289-97.
• 5.Pinto NR, Applebaum MA, Volchenboum SL et al. Advances in Risk Classification and Treatment Strategies for Neuroblastoma. J Clin Oncol. 2015; 20;33(27):3008-17.
• 6.Whittle SB, Smith V, Doherty E, Zhao S, McCarty S, Zage PE. Overview and recent advances in the treatment of neuroblastoma. Expert Rev Anticancer Ther. 2017;17(4):369-386.
• 7.Olgun N, Cecen E, Ince D et al. Dinutuximab beta plus conventional chemotherapy for relapsed/refractory high-risk neuroblastoma: A single-center experience. Front Oncol. 2022; 23; 12:1041443.
• 8.Vega FM, Ridley AJ. Rho GTPases in cancer cell biology.FEBS Lett. 2008; 18;582(14):2093-101.
• 9.Hodge RG, Ridley AJ. Regulating Rho GTPases and their regulators. Nat Rev Mol Cell Biol. 2016;17(8):496-510.
• 10.Svensmark JH, Brakebusch C. Rho GTPases in cancer: friend or foe? Oncogene. 2019;38(50):7447-7456.
• 11.The Cancer Genome Atlas Research Network., Weinstein, J., Collisson, E. et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet 2013; 45, 1113–1120.
• 12.Gómez del Pulgar T, Benitah SA, Valerón PF, Espina C, Lacal JC. Rho GTPase expression in tumourigenesis: evidence for a significant link. Bioessays. 2005; 27(6):602-13.
• 13.Zaoui K, Duhamel S. RhoB as a tumor suppressor: It's all about localization. Eur J Cell Biol. 2023;102(2):151313. doi: 10.1016/j.ejcb.2023.151313.
• 14.Vega FM, Ridley AJ. The RhoB small GTPase in physiology and disease. Small GTPases. 2018; 3,9(5):384-393.
• 15.Ellis S, Mellor H. Regulation of endocytic traffic by rho family GTPases. Trends Cell Biol. 2000;10(3):85-8. doi: 10.1016/s0962-8924(99)01710-9.
• 16.Adini I, Rabinovitz I, Sun JF, Prendergast GC, Benjamin LE.RhoB controls Akt trafficking and stage-specific survival of endothelial cells during vascular development. Genes Dev.2003; 1;17(21):2721-32. doi: 10.1101/gad.1134603.
• 17.Sandilands E, Cans C, Fincham VJ et al. RhoB and actin polymerization coordinate Src activation with endosome-mediated delivery to the membrane. Dev Cell. 2004;7(6):855-69. doi: 10.1016/j.devcel.2004.09.019.
• 18.Gampel A, Parker PJ, Mellor H. Regulation of epidermal growth factor receptor traffic by the small GTPase rhoB. Curr Biol. 1999; 9;9(17):955-8. doi: 10.1016/s0960-9822(99)80422-9.
• 19.Canguilhem B, Pradines A, Baudouin C, Boby C, Lajoie-Mazenc I, Charveron M, Favre G. RhoB protects human keratinocytes from UVB-induced apoptosis through epidermal growth factor receptor signaling. J Biol Chem. 2005;30;280(52):43257-63. doi: 10.1074/jbc.M508650200.
• 20.Tillement V, Lajoie-Mazenc I, Casanova A, Froment C, Penary M, Tovar D, Marquez R, Monsarrat B, Favre G, Pradines A.Phosphorylation of RhoB by CK1 impedes actin stress fiber organization and epidermal growth factor receptor stabilization. Exp Cell Res. 2008;10;314(15):2811-21. doi: 10.1016/j.yexcr.2008.06.011
• 21.Kroon J, Tol S, van Amstel S, Elias JA, Fernandez-Borja M. The small GTPase RhoB regulates TNFα signaling in endothelial cells. PLoS One. 2013; 26,8(9):e75031.
• 22.Gutierrez E, Cahatol I, Bailey CAR et al. Regulation of RhoB Gene Expression during Tumorigenesis and Aging Process and Its Potential Applications in These Processes. Cancers (Basel).2019; 13,11(6):818.
• 23.Mamouni K, Cristini A, Guirouilh-Barbat J et al. RhoB promotes γH2AX dephosphorylation and DNA double-strand break repair. Mol Cell Biol. 2014; 34(16):3144-55.
• 24.Lei C, Li S, Fan Y et al. LncRNA DUXAP8 induces breast cancer radioresistance by modulating the PI3K/AKT/mTORpathway and the EZH2-E-cadherin/RHOB pathway. Cancer Biol Ther. 2022;31;23(1):1-13.
• 25.Zhou J, Zhu Y, Zhang G et al. A distinct role of RhoB in gastric cancer suppression. Int J Cancer. 2011; 1;128(5):1057-68.
• 26.Liu Y, Song N, Ren K et al. Expression loss and revivification of RhoB gene in ovary carcinoma carcinogenesis and development. PLoS ONE 2013; 8, e78417.
• 27.Sato N, Fukui T, Taniguchi T et al. RhoB is frequently downregulated in non-small-cell lung cancer and resides in the 2p24 homozygous deletion region of a lung cancer cell line. IntJ Cancer. 2007;1,120(3):543-51.
• 28.Bousquet E, Calvayrac O, Mazières J et al. RhoB loss inducesRac1-dependent mesenchymal cell invasion in lung cellsthrough PP2A inhibition. Oncogene. 2016;7;35(14):1760-9. doi: 10.1038/onc.2015.240.
• 29.Mazieres J, Antonia T, Daste G et al. Loss of RhoB expression in human lung cancer progression. Clin Cancer Res. 2004;15;10(8):2742-50. doi: 10.1158/1078-0432.ccr-03-0149. PMID: 15102679.
• 30.Ju JA, Godet I, Di Giacomo JW, Gilkes DM. RhoB is regulated by hypoxia and modulates metastasis in breast cancer. Cancer Rep (Hoboken). 2020;3(1):e1164.
• 31.Kopsida M, Liu N, Kotti A et al. RhoB expression associated with chemotherapy response and prognosis in colorectal cancer. Cancer Cell Int. 2024; 15;24(1):75.
• 32.Calvayrac O, Mazières J, Figarol S et al. The RAS-relatedGTPase RHOB confers resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer via an AKT-dependent mechanism. EMBO Mol Med. 2017; 9(2):238-250.
• 33.Kazerounian S, Gerald D, Huang M et al. RhoB differentially controls Akt function in tumor cells and stromal endothelial cells during breast tumorigenesis. Cancer Res. 2013; 1;73(1):50-61. doi: 10.1158/0008-5472.CAN-11-3055.
• 34.Turashvili G, Bouchal J, Baumforth K et al. Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer.2007;27; 7:55. doi: 10.1186/1471-2407-7-55.
• 35.Olgun N, İnce D, Çeçen E et al. The Turkish Pediatric Oncology Group Neuroblastoma Treatment Protocol-2020 1st edition. Inciraltı-İzmir, TPOG, 2020: 1-354.
• 36.Haga RB, Ridley AJ. Rho GTPases: Regulation and roles in cancer cell biology. Small GTPases. 2016;7(4):207-221.
• 37.Sahai, E., Marshall, C. RHO–GTPases and cancer. Nat Rev Cancer 2002; 133–142.
• 38.Dyberg C, Fransson S, Andonova T, Sveinbjörnsson B, Lännerholm-Palm J, Olsen TK, et al. Rho-associated kinase is a therapeutic target in neuroblastoma. Proc Natl Acad Sci. 2017; 8;114(32): E6603-E6612.
• 39.Ju JA, Gilkes DM. RhoB: Team Oncogene or Team Tumor Suppressor? Genes (Basel). 2018; 30;9(2):67.
• 40.MacFarland S, Bagatell R. Advances in neuroblastoma therapy.Curr Opin Pediatr. 2019;31(1):14-20.