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Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

BCL11A Facilitates Cell Proliferation and Metastasis in Neuroblastoma via Regulating the PI3K/Akt Signaling Pathway

Author(s): Qianya Jin, Yanmin Chen, Shibei Du, Dongqing Xu, Juanqing Yue, Lei Cai and Xiaojun Yuan*

Volume 22, Issue 11, 2022

Published on: 29 August, 2022

Page: [919 - 930] Pages: 12

DOI: 10.2174/1568009622666220728123748

open access plus

Abstract

Purpose: The study aims to access the value of B-cell lymphoma/leukemia 11A (BCL11A) in the prognosis of patients with neuroblastoma (NB) and to explore its role and possible mechanism in NB.

Methods: Tumor specimens from 53 children with neuroblastoma were evaluated for the relationship between BCL11A expression level and prognosis of NB patients. Online datasets like SEQC and Asgharzadeh were analyzed to further check out the suppose.The role of BCL11A in the proliferation and migration of NB cells was studied by functional experiments such as CCK8, colony formation, flow cytometry, transwell and wound healing assay after knocking down BCL11A by small interfering RNA (siRNA) in vitro. The protein makers of the potential pathways were tested by western blot.

Results: High expression of BCL11A in NB patients was closely correlated with high-risk and poor prognosis. The proliferation and migration abilities of NB cell lines SK-N-BE(2) and IMR-32 were significantly impaired by silencing BCL11A. Downregulation of BCL11A expression level in NB cells inhibited the epithelial-mesenchymal transition (EMT) process and affected the PI3K/Akt signaling pathway.

Conclusion: As a prognostic indicator of survival in NB patients, BCL11A might serve as a potential therapeutic target. BCL11A played a regulatory role in cell proliferation, invasion, and migration in NB, which may be through the PI3K/AKT signaling pathway and induce EMT

Keywords: Neuroblastoma, BCL11A, prognosis, proliferation, invasion, metastasis.

Graphical Abstract

[1]
Robison, L.L.; Armstrong, G.T.; Boice, J.D.; Chow, E.J.; Davies, S.M.; Donaldson, S.S.; Green, D.M.; Hammond, S.; Meadows, A.T.; Mertens, A.C.; Mulvihill, J.J.; Nathan, P.C.; Neglia, J.P.; Packer, R.J.; Rajaraman, P.; Sklar, C.A.; Stovall, M.; Strong, L.C.; Yasui, Y.; Zeltzer, L.K. The childhood cancer survivor study: A national cancer institute-supported resource for outcome and intervention research. J. Clin. Oncol., 2009, 27(14), 2308-2318.
[http://dx.doi.org/10.1200/JCO.2009.22.3339] [PMID: 19364948]
[2]
Matthay, K.K.; Maris, J.M.; Schleiermacher, G.; Nakagawara, A.; Mackall, C.L.; Diller, L.; Weiss, W.A. Neuroblastoma. Nat. Rev. Dis. Primers, 2016, 2(1), 16078.
[http://dx.doi.org/10.1038/nrdp.2016.78] [PMID: 27830764]
[3]
Pastor, E.R.; Mousa, S.A. Current management of neuroblastoma and future direction. Crit. Rev. Oncol. Hematol., 2019, 138, 38-43.
[http://dx.doi.org/10.1016/j.critrevonc.2019.03.013] [PMID: 31092383]
[4]
Wiegreffe, C.; Simon, R.; Peschkes, K.; Kling, C.; Strehle, M.; Cheng, J.; Srivatsa, S.; Liu, P.; Jenkins, N.A.; Copeland, N.G.; Tarabykin, V.; Britsch, S. Bcl11a (Ctip1) controls migration of cortical projection neurons through regulation of Sema3c. Neuron, 2015, 87(2), 311-325.
[http://dx.doi.org/10.1016/j.neuron.2015.06.023] [PMID: 26182416]
[5]
Satterwhite, E.; Sonoki, T.; Willis, T.G.; Harder, L.; Nowak, R.; Arriola, E.L.; Liu, H.; Price, H.P.; Gesk, S.; Steinemann, D.; Schlegelberger, B.; Oscier, D.G.; Siebert, R.; Tucker, P.W.; Dyer, M.J. The BCL11 gene family: Involvement of BCL11A in lymphoid malignancies. Blood, 2001, 98(12), 3413-3420.
[http://dx.doi.org/10.1182/blood.V98.12.3413] [PMID: 11719382]
[6]
Xu, L.; Wu, H.; Wu, X.; Li, Y.; He, D. The expression pattern of Bcl11a, Mdm2 and Pten genes in B-cell acute lymphoblastic leukemia. Asia Pac. J. Clin. Oncol., 2018, 14(2), e124-e128.
[http://dx.doi.org/10.1111/ajco.12690] [PMID: 28544358]
[7]
Shi, H.; Li, C.; Feng, W.; Yue, J.; Song, J.; Peng, A.; Wang, H. BCL11A is oncogenic and predicts poor outcomes in natural killer/t-cell Lymphoma. Front. Pharmacol., 2020, 11, 820.
[http://dx.doi.org/10.3389/fphar.2020.00820] [PMID: 32625084]
[8]
Zhu, L.; Pan, R.; Zhou, D.; Ye, G.; Tan, W. BCL11A enhances stemness and promotes progression by activating Wnt/β-catenin signaling in breast cancer. Cancer Manag. Res., 2019, 11, 2997-3007.
[http://dx.doi.org/10.2147/CMAR.S199368] [PMID: 31114347]
[9]
Lazarus, K.A.; Hadi, F.; Zambon, E.; Bach, K.; Santolla, M.F.; Watson, J.K.; Correia, L.L.; Das, M.; Ugur, R.; Pensa, S.; Becker, L.; Campos, L.S.; Ladds, G.; Liu, P.; Evan, G.I.; McCaughan, F.M.; Le Quesne, J.; Lee, J.H.; Calado, D.; Khaled, W.T. BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous carcinoma. Nat. Commun., 2018, 9(1), 3327.
[http://dx.doi.org/10.1038/s41467-018-05790-5] [PMID: 30127402]
[10]
Yin, J.; Xie, X.; Ye, Y.; Wang, L.; Che, F. BCL11A: A potential diagnostic biomarker and therapeutic target in human diseases. Biosci. Rep., 2019, 39(11), BSR20190604.
[http://dx.doi.org/10.1042/BSR20190604] [PMID: 31654056]
[11]
Sultan, I.; Tbakhi, A. BCL11A gene over-expression in high risk neuroblastoma. Cancer Genet., 2020, 244, 30-31.
[http://dx.doi.org/10.1016/j.cancergen.2020.02.003] [PMID: 32113148]
[12]
Li, S.H.; Li, J.P.; Chen, L.; Liu, J.L. miR-146a induces apoptosis in neuroblastoma cells by targeting BCL11A. Med. Hypotheses, 2018, 117, 21-27.
[http://dx.doi.org/10.1016/j.mehy.2018.05.019] [PMID: 30077189]
[13]
Zhao, Q.; Wu, Y.M. Expert consensus on diagnosis and treatment of neuroblastoma in children. Zhonghua Xiaoerwaike Zazhi, 2015, 36(1), 3-7.
[14]
Xie, Y.; Xu, H.; Fang, F.; Li, Z.; Zhou, H.; Pan, J.; Guo, W.; Zhu, X.; Wang, J.; Wu, Y. A 3-protein expression signature of neuroblastoma for outcome prediction. Am. J. Surg. Pathol., 2018, 42(8), 1027-1035.
[http://dx.doi.org/10.1097/PAS.0000000000001082] [PMID: 29794872]
[15]
Wu, Y.; Zhou, B.P. New insights of epithelial-mesenchymal transition in cancer metastasis. Acta Biochim. Biophys. Sin. (Shanghai), 2008, 40(7), 643-650.
[http://dx.doi.org/10.1111/j.1745-7270.2008.00443.x] [PMID: 18604456]
[16]
Zhou, J.; Zhou, L.; Zhang, D.; Tang, W.J.; Tang, D.; Shi, X.L.; Yang, Y.; Zhou, L.; Liu, F.; Yu, Y.; Liu, P.; Tao, L.; Lu, L.M. BCL11A promotes the progression of laryngeal squamous cell carcinoma. Front. Oncol., 2020, 10, 375.
[http://dx.doi.org/10.3389/fonc.2020.00375] [PMID: 32266150]
[17]
Wang, X.; Xu, Y.; Xu, K.; Chen, Y.; Xiao, X.; Guan, X. BCL11A confers cell invasion and migration in androgen receptor-positive triple-negative breast cancer. Oncol. Lett., 2020, 19(4), 2916-2924.
[http://dx.doi.org/10.3892/ol.2020.11383] [PMID: 32218847]
[18]
Kaneda, H.; Arao, T.; Tanaka, K.; Tamura, D.; Aomatsu, K.; Kudo, K.; Sakai, K.; De Velasco, M.A.; Matsumoto, K.; Fujita, Y.; Yamada, Y.; Tsurutani, J.; Okamoto, I.; Nakagawa, K.; Nishio, K. FOXQ1 is overexpressed in colorectal cancer and enhances tumorigenicity and tumor growth. Cancer Res., 2010, 70(5), 2053-2063.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-2161] [PMID: 20145154]
[19]
Khaled, W.T.; Choon Lee, S.; Stingl, J.; Chen, X.; Raza Ali, H.; Rueda, O.M.; Hadi, F.; Wang, J.; Yu, Y.; Chin, S.F.; Stratton, M.; Futreal, A.; Jenkins, N.A.; Aparicio, S.; Copeland, N.G.; Watson, C.J.; Caldas, C.; Liu, P. BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells. Nat. Commun., 2015, 6(1), 5987.
[http://dx.doi.org/10.1038/ncomms6987] [PMID: 25574598]
[20]
Hayashi, N.; Manyam, G.C.; Gonzalez-Angulo, A.M.; Niikura, N.; Yamauchi, H.; Nakamura, S.; Hortobágyi, G.N.; Baggerly, K.A.; Ueno, N.T. Reverse-phase protein array for prediction of patients at low risk of developing bone metastasis from breast cancer. Oncologist, 2014, 19(9), 909-914.
[http://dx.doi.org/10.1634/theoncologist.2014-0099] [PMID: 25117064]
[21]
Hass, H.G.; Vogel, U.; Scheurlen, M.; Jobst, J. Use of gene expression analysis for discrimination of primary and secondary adenocarcinoma of the liver. Oncology, 2018, 95(4), 211-219.
[http://dx.doi.org/10.1159/000489563] [PMID: 29920486]
[22]
Zhou, J.; Yang, Y.; Zhang, D.; Zhou, L.; Tao, L.; Lu, L.M. Genetic polymorphisms and plasma levels of BCL11A contribute to the development of laryngeal squamous cell carcinoma. PLoS One, 2017, 12(2), e0171116.
[http://dx.doi.org/10.1371/journal.pone.0171116] [PMID: 28225775]
[23]
Boelens, M.C.; Kok, K.; van der Vlies, P.; van der Vries, G.; Sietsma, H.; Timens, W.; Postma, D.S.; Groen, H.J.; van den Berg, A. Genomic aberrations in squamous cell lung carcinoma related to lymph node or distant metastasis. Lung Cancer, 2009, 66(3), 372-378.
[http://dx.doi.org/10.1016/j.lungcan.2009.02.017] [PMID: 19324446]
[24]
Zhang, X.; Wang, L.; Wang, Y.; Shi, S.; Zhu, H.; Xiao, F.; Yang, J.; Yang, A.; Hao, X. Inhibition of FOXQ1 induces apoptosis and suppresses proliferation in prostate cancer cells by controlling BCL11A/MDM2 expression. Oncol. Rep., 2016, 36(4), 2349-2356.
[http://dx.doi.org/10.3892/or.2016.5018] [PMID: 27573292]
[25]
Fulda, S. The PI3K/Akt/mTOR pathway as therapeutic target in neuroblastoma. Curr. Cancer Drug Targets, 2009, 9(6), 729-737.
[http://dx.doi.org/10.2174/156800909789271521] [PMID: 19754357]
[26]
King, D.; Yeomanson, D.; Bryant, H.E. PI3King the lock: Targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. J. Pediatr. Hematol. Oncol., 2015, 37(4), 245-251.
[http://dx.doi.org/10.1097/MPH.0000000000000329] [PMID: 25811750]
[27]
Zafar, A.; Wang, W.; Liu, G.; Wang, X.; Xian, W.; McKeon, F.; Foster, J.; Zhou, J.; Zhang, R. Molecular targeting therapies for neuroblastoma: Progress and challenges. Med. Res. Rev., 2021, 41(2), 961-1021.
[http://dx.doi.org/10.1002/med.21750] [PMID: 33155698]
[28]
Braoudaki, M.; Hatziagapiou, K.; Zaravinos, A.; Lambrou, G.I. MYCN in neuroblastoma: “old wine into new wineskins”. Diseases, 2021, 9(4), 78.
[http://dx.doi.org/10.3390/diseases9040078] [PMID: 34842635]
[29]
Harenza, J.L.; Diamond, M.A.; Adams, R.N.; Song, M.M.; Davidson, H.L.; Hart, L.S.; Dent, M.H.; Fortina, P.; Reynolds, C.P.; Maris, J.M. Transcriptomic profiling of 39 commonly-used neuroblastoma cell lines. Sci. Data, 2017, 4(1), 170033.
[http://dx.doi.org/10.1038/sdata.2017.33] [PMID: 28350380]
[30]
Ward, E.; DeSantis, C.; Robbins, A.; Kohler, B.; Jemal, A. Childhood and adolescent cancer statistics, 2014. CA Cancer J. Clin., 2014, 64(2), 83-103.
[http://dx.doi.org/10.3322/caac.21219] [PMID: 24488779]

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