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Published in: Cancer Cell International 1/2020

Open Access 01-12-2020 | Primary research

BORA regulates cell proliferation and migration in bladder cancer

Authors: Songtao Cheng, Tianchen Peng, Xiaolu Zhu, Fenfang Zhou, Gang Wang, Lingao Ju, Yu Xiao, Xuefeng Liu, Xinghuan Wang

Published in: Cancer Cell International | Issue 1/2020

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Abstract

Background

Bladder cancer is having a gradually increasing incidence in China. Except for the traditional chemotherapy drugs, there are no emerging new drugs for almost 30 years in bladder cancer. New potential therapeutic targets and biomarkers are urgently needed.

Methods

BORA is the activator of kinase Aurora A and plays an important role in cell cycle progression. To investigate the function of BORA in BCa, we established BORA knockdown and overexpression cell models for in vitro studies, xenograft and pulmonary metastasis mouse models for in vivo studies.

Results

Our results indicated that BORA was upregulated in human bladder cancer (BCa) compared to the normal bladder and paracancerous tissues at transcriptional and translational levels. We found that BORA was positively related to BCa cell proliferation. Furthermore, BORA knockdown induced cell cycle arrest in G2/M phase while BORA overexpression decreased the proportion of cells in G2/M, associated with PLK1–CDC25C–CDK1 alteration. Interestingly, we observed that knockdown of BORA inhibited BCa cell migration and invasion, accompanied with alterations of epithelial–mesenchymal transition (EMT) pathway related proteins. In vivo studies confirmed the inhibition effect of BORA knockdown on BCa cell growth and migration.

Conclusions

Our study indicates that BORA regulates BCa cell cycle and growth, meanwhile influences cell motility by EMT, and could be a novel biomarker and potential therapeutic target in BCa.
Appendix
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Literature
1.
go back to reference Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71(1):96–108.CrossRef Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71(1):96–108.CrossRef
2.
go back to reference Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.CrossRef Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.CrossRef
3.
go back to reference Prasad SM, Decastro GJ, Steinberg GD. Medscape: urothelial carcinoma of the bladder: definition, treatment and future efforts. Nat Rev Urol. 2011;8(11):631–42.CrossRef Prasad SM, Decastro GJ, Steinberg GD. Medscape: urothelial carcinoma of the bladder: definition, treatment and future efforts. Nat Rev Urol. 2011;8(11):631–42.CrossRef
4.
go back to reference Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67–76.CrossRef Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67–76.CrossRef
5.
go back to reference Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26.CrossRef Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26.CrossRef
6.
go back to reference Sonpavde G. PD-1 and PD-L1 inhibitors as salvage therapy for urothelial carcinoma. N Engl J Med. 2017;376(11):1073–4.CrossRef Sonpavde G. PD-1 and PD-L1 inhibitors as salvage therapy for urothelial carcinoma. N Engl J Med. 2017;376(11):1073–4.CrossRef
7.
go back to reference Zhang Z, Zhang G, Kong C. Targeted inhibition of Polo-like kinase 1 by a novel small-molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells. J Cell Mol Med. 2017;21(4):758–67.CrossRef Zhang Z, Zhang G, Kong C. Targeted inhibition of Polo-like kinase 1 by a novel small-molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells. J Cell Mol Med. 2017;21(4):758–67.CrossRef
8.
go back to reference Hutterer A, Berdnik D, Wirtz-Peitz F, Zigman M, Schleiffer A, Knoblich JA. Mitotic activation of the kinase Aurora-A requires its binding partner Bora. Dev Cell. 2006;11(2):147–57.CrossRef Hutterer A, Berdnik D, Wirtz-Peitz F, Zigman M, Schleiffer A, Knoblich JA. Mitotic activation of the kinase Aurora-A requires its binding partner Bora. Dev Cell. 2006;11(2):147–57.CrossRef
9.
go back to reference Bruinsma W, Aprelia M, Garcia-Santisteban I, Kool J, Xu YJ, Medema RH. Inhibition of Polo-like kinase 1 during the DNA damage response is mediated through loss of Aurora A recruitment by Bora. Oncogene. 2017;36(13):1840–8.CrossRef Bruinsma W, Aprelia M, Garcia-Santisteban I, Kool J, Xu YJ, Medema RH. Inhibition of Polo-like kinase 1 during the DNA damage response is mediated through loss of Aurora A recruitment by Bora. Oncogene. 2017;36(13):1840–8.CrossRef
10.
go back to reference van Vugt MA, Bras A, Medema RH. Polo-like kinase-1 controls recovery from a G2 DNA damage-induced arrest in mammalian cells. Mol Cell. 2004;15(5):799–811.CrossRef van Vugt MA, Bras A, Medema RH. Polo-like kinase-1 controls recovery from a G2 DNA damage-induced arrest in mammalian cells. Mol Cell. 2004;15(5):799–811.CrossRef
11.
go back to reference Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRef Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRef
12.
go back to reference Ju LG, Zhu Y, Long QY, Li XJ, Lin X, Tang SB, Yin L, Xiao Y, Wang XH, Li L, et al. SPOP suppresses prostate cancer through regulation of CYCLIN E1 stability. Cell Death Differ. 2019;26(6):1156–68.CrossRef Ju LG, Zhu Y, Long QY, Li XJ, Lin X, Tang SB, Yin L, Xiao Y, Wang XH, Li L, et al. SPOP suppresses prostate cancer through regulation of CYCLIN E1 stability. Cell Death Differ. 2019;26(6):1156–68.CrossRef
13.
go back to reference Zhou N, Singh K, Mir MC, Parker Y, Lindner D, Dreicer R, Ecsedy JA, Zhang Z, Teh BT, Almasan A, et al. The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell-cycle progression in malignant bladder cancer cells in vitro and in vivo. Clin Cancer Res. 2013;19(7):1717–28.CrossRef Zhou N, Singh K, Mir MC, Parker Y, Lindner D, Dreicer R, Ecsedy JA, Zhang Z, Teh BT, Almasan A, et al. The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell-cycle progression in malignant bladder cancer cells in vitro and in vivo. Clin Cancer Res. 2013;19(7):1717–28.CrossRef
14.
go back to reference Gjertsen BT, Schoffski P. Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy. Leukemia. 2015;29(1):11–9.CrossRef Gjertsen BT, Schoffski P. Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy. Leukemia. 2015;29(1):11–9.CrossRef
15.
go back to reference Graff JN, Higano CS, Hahn NM, Taylor MH, Zhang B, Zhou X, Venkatakrishnan K, Leonard EJ, Sarantopoulos J. Open-label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors. Cancer. 2016;122(16):2524–33.CrossRef Graff JN, Higano CS, Hahn NM, Taylor MH, Zhang B, Zhou X, Venkatakrishnan K, Leonard EJ, Sarantopoulos J. Open-label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors. Cancer. 2016;122(16):2524–33.CrossRef
16.
go back to reference Pujade-Lauraine E, Selle F, Weber B, Ray-Coquard IL, Vergote I, Sufliarsky J, Del Campo JM, Lortholary A, Lesoin A, Follana P, et al. Volasertib Versus chemotherapy in platinum-resistant or -refractory ovarian cancer: a randomized phase II Groupe des Investigateurs Nationaux pour l’Etude des Cancers de l’Ovaire Study. J Clin Oncol. 2016;34(7):706–13.CrossRef Pujade-Lauraine E, Selle F, Weber B, Ray-Coquard IL, Vergote I, Sufliarsky J, Del Campo JM, Lortholary A, Lesoin A, Follana P, et al. Volasertib Versus chemotherapy in platinum-resistant or -refractory ovarian cancer: a randomized phase II Groupe des Investigateurs Nationaux pour l’Etude des Cancers de l’Ovaire Study. J Clin Oncol. 2016;34(7):706–13.CrossRef
17.
go back to reference Cirillo L, Thomas Y, Pintard L, Gotta M. BORA-dependent PLK1 regulation: a new weapon for cancer therapy? Mol Cell Oncol. 2016;3(5):e1199265.CrossRef Cirillo L, Thomas Y, Pintard L, Gotta M. BORA-dependent PLK1 regulation: a new weapon for cancer therapy? Mol Cell Oncol. 2016;3(5):e1199265.CrossRef
18.
go back to reference Zhang QX, Gao R, Xiang J, Yuan ZY, Qian YM, Yan M, Wang ZF, Liu Q, Zhao HD, Liu CH. Cell cycle protein Bora serves as a novel poor prognostic factor in multiple adenocarcinomas. Oncotarget. 2017;8(27):43838–52.CrossRef Zhang QX, Gao R, Xiang J, Yuan ZY, Qian YM, Yan M, Wang ZF, Liu Q, Zhao HD, Liu CH. Cell cycle protein Bora serves as a novel poor prognostic factor in multiple adenocarcinomas. Oncotarget. 2017;8(27):43838–52.CrossRef
19.
go back to reference Cairns J, Peng Y, Yee VC, Lou Z, Wang L. Bora downregulation results in radioresistance by promoting repair of double strand breaks. PLoS ONE. 2015;10(3):e0119208.CrossRef Cairns J, Peng Y, Yee VC, Lou Z, Wang L. Bora downregulation results in radioresistance by promoting repair of double strand breaks. PLoS ONE. 2015;10(3):e0119208.CrossRef
20.
go back to reference Parrilla A, Cirillo L, Thomas Y, Gotta M, Pintard L, Santamaria A. Mitotic entry: the interplay between Cdk1, Plk1 and Bora. Cell Cycle. 2016;15(23):3177–82.CrossRef Parrilla A, Cirillo L, Thomas Y, Gotta M, Pintard L, Santamaria A. Mitotic entry: the interplay between Cdk1, Plk1 and Bora. Cell Cycle. 2016;15(23):3177–82.CrossRef
21.
go back to reference Wang G, Cao R, Wang Y, Qian G, Dan HC, Jiang W, Ju L, Wu M, Xiao Y, Wang X. Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARgamma signalling pathway. Sci Rep. 2016;6:35783.CrossRef Wang G, Cao R, Wang Y, Qian G, Dan HC, Jiang W, Ju L, Wu M, Xiao Y, Wang X. Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARgamma signalling pathway. Sci Rep. 2016;6:35783.CrossRef
22.
go back to reference Cheng S, Wang G, Wang Y, Cai L, Qian K, Ju L, Liu X, Xiao Y, Wang X. Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPARgamma-mediated pathway in bladder cancer. Clin Sci (Lond). 2019;133(15):1745–58.CrossRef Cheng S, Wang G, Wang Y, Cai L, Qian K, Ju L, Liu X, Xiao Y, Wang X. Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPARgamma-mediated pathway in bladder cancer. Clin Sci (Lond). 2019;133(15):1745–58.CrossRef
23.
go back to reference Cao R, Wang G, Qian K, Chen L, Ju L, Qian G, Wu CL, Dan HC, Jiang W, Wu M, et al. TM4SF1 regulates apoptosis, cell cycle and ROS metabolism via the PPARgamma-SIRT1 feedback loop in human bladder cancer cells. Cancer Lett. 2018;414:278–93.CrossRef Cao R, Wang G, Qian K, Chen L, Ju L, Qian G, Wu CL, Dan HC, Jiang W, Wu M, et al. TM4SF1 regulates apoptosis, cell cycle and ROS metabolism via the PPARgamma-SIRT1 feedback loop in human bladder cancer cells. Cancer Lett. 2018;414:278–93.CrossRef
24.
go back to reference Lu M, Ge Q, Wang G, Luo Y, Wang X, Jiang W, Liu X, Wu CL, Xiao Y, Wang X. CIRBP is a novel oncogene in human bladder cancer inducing expression of HIF-1alpha. Cell Death Dis. 2018;9(10):1046.CrossRef Lu M, Ge Q, Wang G, Luo Y, Wang X, Jiang W, Liu X, Wu CL, Xiao Y, Wang X. CIRBP is a novel oncogene in human bladder cancer inducing expression of HIF-1alpha. Cell Death Dis. 2018;9(10):1046.CrossRef
25.
go back to reference Cheng S, Qian K, Wang Y, Wang G, Liu X, Xiao Y, Wang X. PPARgamma inhibition regulates the cell cycle, proliferation and motility of bladder cancer cells. J Cell Mol Med. 2019;23(5):3724–36.CrossRef Cheng S, Qian K, Wang Y, Wang G, Liu X, Xiao Y, Wang X. PPARgamma inhibition regulates the cell cycle, proliferation and motility of bladder cancer cells. J Cell Mol Med. 2019;23(5):3724–36.CrossRef
26.
go back to reference Zhou Q, Chen S, Lu M, Luo Y, Wang G, Xiao Y, Ju L, Wang X. EFEMP2 suppresses epithelial-mesenchymal transition via Wnt/beta-catenin signaling pathway in human bladder cancer. Int J Biol Sci. 2019;15(10):2139–55.CrossRef Zhou Q, Chen S, Lu M, Luo Y, Wang G, Xiao Y, Ju L, Wang X. EFEMP2 suppresses epithelial-mesenchymal transition via Wnt/beta-catenin signaling pathway in human bladder cancer. Int J Biol Sci. 2019;15(10):2139–55.CrossRef
27.
go back to reference Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98–102.CrossRef Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98–102.CrossRef
28.
go back to reference Cuylen S, Blaukopf C, Politi AZ, Muller-Reichert T, Neumann B, Poser I, Ellenberg J, Hyman AA, Gerlich DW. Ki-67 acts as a biological surfactant to disperse mitotic chromosomes. Nature. 2016;535(7611):308–12.CrossRef Cuylen S, Blaukopf C, Politi AZ, Muller-Reichert T, Neumann B, Poser I, Ellenberg J, Hyman AA, Gerlich DW. Ki-67 acts as a biological surfactant to disperse mitotic chromosomes. Nature. 2016;535(7611):308–12.CrossRef
29.
go back to reference Zaidi SK, Young DW, Montecino MA, Lian JB, van Wijnen AJ, Stein JL, Stein GS. Mitotic bookmarking of genes: a novel dimension to epigenetic control. Nat Rev Genet. 2010;11(8):583–9.CrossRef Zaidi SK, Young DW, Montecino MA, Lian JB, van Wijnen AJ, Stein JL, Stein GS. Mitotic bookmarking of genes: a novel dimension to epigenetic control. Nat Rev Genet. 2010;11(8):583–9.CrossRef
30.
go back to reference Kumagai A, Dunphy WG. Purification and molecular cloning of Plx1, a Cdc25-regulatory kinase from Xenopus egg extracts. Science. 1996;273(5280):1377–80.CrossRef Kumagai A, Dunphy WG. Purification and molecular cloning of Plx1, a Cdc25-regulatory kinase from Xenopus egg extracts. Science. 1996;273(5280):1377–80.CrossRef
31.
go back to reference Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9(6):400–14.CrossRef Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9(6):400–14.CrossRef
32.
go back to reference Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18(2):128–34.CrossRef Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18(2):128–34.CrossRef
33.
go back to reference Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, Clouin C, Taylor SS, Yaffe MB, Medema RH. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature. 2008;455(7209):119–23.CrossRef Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, Clouin C, Taylor SS, Yaffe MB, Medema RH. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature. 2008;455(7209):119–23.CrossRef
34.
go back to reference Jang YJ, Ma S, Terada Y, Erikson RL. Phosphorylation of threonine 210 and the role of serine 137 in the regulation of mammalian polo-like kinase. J Biol Chem. 2002;277(46):44115–20.CrossRef Jang YJ, Ma S, Terada Y, Erikson RL. Phosphorylation of threonine 210 and the role of serine 137 in the regulation of mammalian polo-like kinase. J Biol Chem. 2002;277(46):44115–20.CrossRef
35.
go back to reference Seki A, Coppinger JA, Jang CY, Yates JR, Fang G. Bora and the kinase Aurora a cooperatively activate the kinase Plk1 and control mitotic entry. Science. 2008;320(5883):1655–8.CrossRef Seki A, Coppinger JA, Jang CY, Yates JR, Fang G. Bora and the kinase Aurora a cooperatively activate the kinase Plk1 and control mitotic entry. Science. 2008;320(5883):1655–8.CrossRef
36.
go back to reference Chan EH, Santamaria A, Sillje HH, Nigg EA. Plk1 regulates mitotic Aurora A function through betaTrCP-dependent degradation of hBora. Chromosoma. 2008;117(5):457–69.CrossRef Chan EH, Santamaria A, Sillje HH, Nigg EA. Plk1 regulates mitotic Aurora A function through betaTrCP-dependent degradation of hBora. Chromosoma. 2008;117(5):457–69.CrossRef
37.
go back to reference Thomas Y, Cirillo L, Panbianco C, Martino L, Tavernier N, Schwager F, Van Hove L, Joly N, Santamaria A, Pintard L, et al. Cdk1 phosphorylates SPAT-1/Bora to promote Plk1 activation in C. elegans and human cells. Cell Rep. 2016;15(3):510–8.CrossRef Thomas Y, Cirillo L, Panbianco C, Martino L, Tavernier N, Schwager F, Van Hove L, Joly N, Santamaria A, Pintard L, et al. Cdk1 phosphorylates SPAT-1/Bora to promote Plk1 activation in C. elegans and human cells. Cell Rep. 2016;15(3):510–8.CrossRef
38.
go back to reference Lee YC, Liao PC, Liou YC, Hsiao M, Huang CY, Lu PJ. Glycogen synthase kinase 3 beta activity is required for hBora/Aurora A-mediated mitotic entry. Cell Cycle. 2013;12(6):953–60.CrossRef Lee YC, Liao PC, Liou YC, Hsiao M, Huang CY, Lu PJ. Glycogen synthase kinase 3 beta activity is required for hBora/Aurora A-mediated mitotic entry. Cell Cycle. 2013;12(6):953–60.CrossRef
39.
go back to reference Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20(2):69–84.CrossRef Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20(2):69–84.CrossRef
40.
go back to reference Lens SM, Voest EE, Medema RH. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer. 2010;10(12):825–41.CrossRef Lens SM, Voest EE, Medema RH. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer. 2010;10(12):825–41.CrossRef
Metadata
Title
BORA regulates cell proliferation and migration in bladder cancer
Authors
Songtao Cheng
Tianchen Peng
Xiaolu Zhu
Fenfang Zhou
Gang Wang
Lingao Ju
Yu Xiao
Xuefeng Liu
Xinghuan Wang
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01392-8

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