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Current Cancer Drug Targets

Editor-in-Chief

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

Research Article

ASPM Predicts Poor Clinical Outcome and Promotes Tumorigenesis for Diffuse Large B-cell Lymphoma

Author(s): Jingjing Wu, Zhengmei He, Yaning Zhu, Chao Jiang, Yuan Deng and Bin Wei*

Volume 21, Issue 1, 2021

Published on: 15 September, 2020

Page: [80 - 89] Pages: 10

DOI: 10.2174/1568009620666200915090703

Price: $65

Abstract

Background: Abnormal spindle-like microcephaly-associated protein (ASPM) has been implicated in the aggressive behavior of several malignant tumors. However, its potential effects on diffuse large B-cell lymphoma (DLBCL) still remain unknown.

Methods: ASPM levels were determined by immunohistochemically in DLBCL tissues from 54 patients and 15 reactive lymphoid hyperplasia (RLH) tissues as control, and its association with clinical features and overall survival were evaluated. The effects of ASPM on cell growth, cell apoptosis and cell cycle of DLBCL cells were assessed. Bioinformatics, quantitative RT-PCR and western blotting were conducted for mechanic investigation.

Results: ASPM expression was upregulated in DLBCL tissues compared with RLH tissues. Its high expression was correlated with inferior clinicopathological characteristics and poor outcomes of DLBCL patients. Multivariate analysis revealed that high ASPM expression emerged as an independent factor for poor prognosis. In DLBCL cell lines, silencing of ASPM suppressed cell growth, induced cell apoptosis and arrested the cell cycle. Mechanically, effects of ASPM knockdown on DLBCL cells were partially dependent on its block of the Wnt/β-catenin pathway.

Conclusion: Collectively, our results suggested that ASPM potentially served as a predictive biomarker of DLCBL tumorigenesis and prognosis, representing a potential therapeutic target for DLCBL.

Keywords: ASPM, diffuse large B-cell lymphoma, biomarker, prognosis, cell growth, tumorigenesis.

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[1]
Campo, E.; Swerdlow, S.H.; Harris, N.L.; Pileri, S.; Stein, H.; Jaffe, E.S. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood, 2011, 117(19), 5019-5032.
[http://dx.doi.org/10.1182/blood-2011-01-293050] [PMID: 21300984]
[2]
van de Schans, S.A.; Wymenga, A.N.; van Spronsen, D.J.; Schouten, H.C.; Coebergh, J.W.; Janssen-Heijnen, M.L. Two sides of the medallion: poor treatment tolerance but better survival by standard chemotherapy in elderly patients with advanced-stage diffuse large B-cell lymphoma. Ann. Oncol., 2012, 23(5), 1280-1286.
[http://dx.doi.org/10.1093/annonc/mdr411] [PMID: 21948810]
[3]
Ripoll, P.; Pimpinelli, S.; Valdivia, M.M.; Avila, J. A cell division mutant of Drosophila with a functionally abnormal spindle. Cell, 1985, 41(3), 907-912.
[http://dx.doi.org/10.1016/S0092-8674(85)80071-4] [PMID: 3924413]
[4]
Kouprina, N.; Pavlicek, A.; Collins, N.K.; Nakano, M.; Noskov, V.N.; Ohzeki, J.; Mochida, G.H.; Risinger, J.I.; Goldsmith, P.; Gunsior, M.; Solomon, G.; Gersch, W.; Kim, J.H.; Barrett, J.C.; Walsh, C.A.; Jurka, J.; Masumoto, H.; Larionov, V. The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein. Hum. Mol. Genet., 2005, 14(15), 2155-2165.
[http://dx.doi.org/10.1093/hmg/ddi220] [PMID: 15972725]
[5]
Paramasivam, M.; Chang, Y.J.; LoTurco, J.J. ASPM and citron kinase co-localize to the midbody ring during cytokinesis. Cell Cycle, 2007, 6(13), 1605-1612.
[http://dx.doi.org/10.4161/cc.6.13.4356] [PMID: 17534152]
[6]
Higgins, J.; Midgley, C.; Bergh, A.M.; Bell, S.M.; Askham, J.M.; Roberts, E.; Binns, R.K.; Sharif, S.M.; Bennett, C.; Glover, D.M.; Woods, C.G.; Morrison, E.E.; Bond, J. Human ASPM participates in spindle organisation, spindle orientation and cytokinesis. BMC Cell Biol., 2010, 11, 85.
[http://dx.doi.org/10.1186/1471-2121-11-85] [PMID: 21044324]
[7]
van der Voet, M.; Berends, C.W.; Perreault, A.; Nguyen-Ngoc, T.; Gönczy, P.; Vidal, M.; Boxem, M.; van den Heuvel, S. NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote meiotic spindle rotation independently of cortical LIN-5/GPR/Galpha. Nat. Cell Biol., 2009, 11(3), 269-277.
[http://dx.doi.org/10.1038/ncb1834] [PMID: 19219036]
[8]
Pulvers, J.N.; Bryk, J.; Fish, J.L.; Wilsch-Bräuninger, M.; Arai, Y.; Schreier, D.; Naumann, R.; Helppi, J.; Habermann, B.; Vogt, J.; Nitsch, R.; Tóth, A.; Enard, W.; Pääbo, S.; Huttner, W.B. Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline. Proc. Natl. Acad. Sci. USA, 2010, 107(38), 16595-16600.
[http://dx.doi.org/10.1073/pnas.1010494107] [PMID: 20823249]
[9]
Bond, J.; Scott, S.; Hampshire, D.J.; Springell, K.; Corry, P.; Abramowicz, M.J.; Mochida, G.H.; Hennekam, R.C.; Maher, E.R.; Fryns, J.P.; Alswaid, A.; Jafri, H.; Rashid, Y.; Mubaidin, A.; Walsh, C.A.; Roberts, E.; Woods, C.G. Protein-truncating mutations in ASPM cause variable reduction in brain size. Am. J. Hum. Genet., 2003, 73(5), 1170-1177.
[http://dx.doi.org/10.1086/379085] [PMID: 14574646]
[10]
Kouprina, N.; Pavlicek, A.; Mochida, G.H.; Solomon, G.; Gersch, W.; Yoon, Y.H.; Collura, R.; Ruvolo, M.; Barrett, J.C.; Woods, C.G.; Walsh, C.A.; Jurka, J.; Larionov, V. Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion. PLoS Biol., 2004, 2(5)E126
[http://dx.doi.org/10.1371/journal.pbio.0020126] [PMID: 15045028]
[11]
Johnson, M.B.; Sun, X.; Kodani, A.; Borges-Monroy, R.; Girskis, K.M.; Ryu, S.C.; Wang, P.P.; Patel, K.; Gonzalez, D.M.; Woo, Y.M.; Yan, Z.; Liang, B.; Smith, R.S.; Chatterjee, M.; Coman, D.; Papademetris, X.; Staib, L.H.; Hyder, F.; Mandeville, J.B.; Grant, P.E.; Im, K.; Kwak, H.; Engelhardt, J.F.; Walsh, C.A.; Bae, B.I. Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size. Nature, 2018, 556(7701), 370-375.
[http://dx.doi.org/10.1038/s41586-018-0035-0] [PMID: 29643508]
[12]
Lin, S.Y.; Pan, H.W.; Liu, S.H.; Jeng, Y.M.; Hu, F.C.; Peng, S.Y.; Lai, P.L.; Hsu, H.C. ASPM is a novel marker for vascular invasion, early recurrence, and poor prognosis of hepatocellular carcinoma. Clin. Cancer Res., 2008, 14(15), 4814-4820.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-5262] [PMID: 18676753]
[13]
Bikeye, S.N.; Colin, C.; Marie, Y.; Vampouille, R.; Ravassard, P.; Rousseau, A.; Boisselier, B.; Idbaih, A.; Calvo, C.F.; Leuraud, P.; Lassalle, M.; El Hallani, S.; Delattre, J.Y.; Sanson, M. ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target. Cancer Cell Int., 2010, 10, 1.
[http://dx.doi.org/10.1186/1475-2867-10-1] [PMID: 20142996]
[14]
Brüning-Richardson, A.; Bond, J.; Alsiary, R.; Richardson, J.; Cairns, D.A.; McCormack, L.; Hutson, R.; Burns, P.; Wilkinson, N.; Hall, G.D.; Morrison, E.E.; Bell, S.M. ASPM and microcephalin expression in epithelial ovarian cancer correlates with tumour grade and survival. Br. J. Cancer, 2011, 104(10), 1602-1610.
[http://dx.doi.org/10.1038/bjc.2011.117] [PMID: 21505456]
[15]
Pai, V.C.; Hsu, C.C.; Chan, T.S.; Liao, W.Y.; Chuu, C.P.; Chen, W.Y.; Li, C.R.; Lin, C.Y.; Huang, S.P.; Chen, L.T.; Tsai, K.K. ASPM promotes prostate cancer stemness and progression by augmenting Wnt-Dvl-3-β-catenin signaling. Oncogene, 2018.
[PMID: 30266990]
[16]
Xu, Z.; Zhang, Q.; Luh, F.; Jin, B.; Liu, X. Overexpression of the ASPM gene is associated with aggressiveness and poor outcome in bladder cancer. Oncol. Lett., 2019, 17(2), 1865-1876.
[PMID: 30675249]
[17]
Bouska, A.; Bi, C.; Lone, W.; Zhang, W.; Kedwaii, A.; Heavican, T.; Lachel, C.M.; Yu, J.; Ferro, R.; Eldorghamy, N.; Greiner, T.C.; Vose, J.; Weisenburger, D.D.; Gascoyne, R.D.; Rosenwald, A.; Ott, G.; Campo, E.; Rimsza, L.M.; Jaffe, E.S.; Braziel, R.M.; Siebert, R.; Miles, R.R.; Dave, S.; Reddy, A.; Delabie, J.; Staudt, L.M.; Song, J.Y.; McKeithan, T.W.; Fu, K.; Green, M.; Chan, W.C.; Iqbal, J. Adult high-grade B-cell lymphoma with Burkitt lymphoma signature: genomic features and potential therapeutic targets. Blood, 2017, 130(16), 1819-1831.
[http://dx.doi.org/10.1182/blood-2017-02-767335] [PMID: 28801451]
[18]
Schrader, A.; Meyer, K.; Walther, N.; Stolz, A.; Feist, M.; Hand, E.; von Bonin, F.; Evers, M.; Kohler, C.; Shirneshan, K.; Vockerodt, M.; Klapper, W.; Szczepanowski, M.; Murray, P.G.; Bastians, H.; Trümper, L.; Spang, R.; Kube, D. Identification of a new gene regulatory circuit involving B cell receptor activated signaling using a combined analysis of experimental, clinical and global gene expression data. Oncotarget, 2016, 7(30), 47061-47081.
[http://dx.doi.org/10.18632/oncotarget.9219] [PMID: 27166259]
[19]
Rhodes, D.R.; Yu, J.; Shanker, K.; Deshpande, N.; Varambally, R.; Ghosh, D.; Barrette, T.; Pandey, A.; Chinnaiyan, A.M. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia, 2004, 6(1), 1-6.
[http://dx.doi.org/10.1016/S1476-5586(04)80047-2] [PMID: 15068665]
[20]
Edgar, R.; Domrachev, M.; Lash, A.E. Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res., 2002, 30(1), 207-210.
[http://dx.doi.org/10.1093/nar/30.1.207] [PMID: 11752295]
[21]
Gao, J.; Aksoy, B.A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S.O.; Sun, Y.; Jacobsen, A.; Sinha, R.; Larsson, E.; Cerami, E.; Sander, C.; Schultz, N. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal., 2013, 6(269), pl1.
[http://dx.doi.org/10.1126/scisignal.2004088] [PMID: 23550210]
[22]
Kanehisa, M. The KEGG database. Novartis Found Symp, 2002, 247, 91-101. discussion 101-103, 119-128, 244-252.
[http://dx.doi.org/10.1002/0470857897.ch8]
[23]
Huang, D.W.; Sherman, B.T.; Tan, Q.; Collins, J.R.; Alvord, W.G.; Roayaei, J.; Stephens, R.; Baseler, M.W.; Lane, H.C.; Lempicki, R.A. The DAVID gene functional classification tool: a novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol., 2007, 8(9), R183.
[http://dx.doi.org/10.1186/gb-2007-8-9-r183] [PMID: 17784955]
[24]
Cheson, B.D.; Pfistner, B.; Juweid, M.E.; Gascoyne, R.D.; Specht, L.; Horning, S.J.; Coiffier, B.; Fisher, R.I.; Hagenbeek, A.; Zucca, E.; Rosen, S.T.; Stroobants, S.; Lister, T.A.; Hoppe, R.T.; Dreyling, M.; Tobinai, K.; Vose, J.M.; Connors, J.M.; Federico, M.; Diehl, V. International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J. Clin. Oncol., 2007, 25(5), 579-586.
[http://dx.doi.org/10.1200/JCO.2006.09.2403] [PMID: 17242396]
[25]
Chen, X.; Huang, L.; Yang, Y.; Chen, S.; Sun, J.; Ma, C.; Xie, J.; Song, Y.; Yang, J. ASPM promotes glioblastoma growth by regulating G1 restriction point progression and Wnt-β-catenin signaling. Aging (Albany NY), 2020, 12(1), 224-241.
[http://dx.doi.org/10.18632/aging.102612] [PMID: 31905171]
[26]
Hsu, C.C.; Liao, W.Y.; Chan, T.S.; Chen, W.Y.; Lee, C.T.; Shan, Y.S.; Huang, P.J.; Hou, Y.C.; Li, C.R.; Tsai, K.K. The differential distributions of ASPM isoforms and their roles in Wnt signaling, cell cycle progression, and pancreatic cancer prognosis. J. Pathol., 2019, 249(4), 498-508.
[http://dx.doi.org/10.1002/path.5341] [PMID: 31465125]
[27]
Li, S.; Young, K.H.; Medeiros, L.J. Diffuse large B-cell lymphoma. Pathology, 2018, 50(1), 74-87.
[http://dx.doi.org/10.1016/j.pathol.2017.09.006] [PMID: 29167021]
[28]
Xie, J.J.; Zhuo, Y.J.; Zheng, Y.; Mo, R.J.; Liu, Z.Z.; Li, B.W.; Cai, Z.D.; Zhu, X.J.; Liang, Y.X.; He, H.C.; Zhong, W.D. High expression of ASPM correlates with tumor progression and predicts poor outcome in patients with prostate cancer. Int. Urol. Nephrol., 2017, 49(5), 817-823.
[http://dx.doi.org/10.1007/s11255-017-1545-7] [PMID: 28213802]
[29]
Kato, T.A.; Okayasu, R.; Jeggo, P.A.; Fujimori, A. ASPM influences DNA double-strand break repair and represents a potential target for radiotherapy. Int. J. Radiat. Biol., 2011, 87(12), 1189-1195.
[http://dx.doi.org/10.3109/09553002.2011.624152] [PMID: 21923303]
[30]
Woods, D.; Turchi, J.J. Chemotherapy induced DNA damage response: convergence of drugs and pathways. Cancer Biol. Ther., 2013, 14(5), 379-389.
[http://dx.doi.org/10.4161/cbt.23761] [PMID: 23380594]
[31]
Nusse, R.; Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell, 2017, 169(6), 985-999.
[http://dx.doi.org/10.1016/j.cell.2017.05.016] [PMID: 28575679]
[32]
Buchman, J.J.; Durak, O.; Tsai, L.H. ASPM regulates Wnt signaling pathway activity in the developing brain. Genes Dev., 2011, 25(18), 1909-1914.
[http://dx.doi.org/10.1101/gad.16830211] [PMID: 21937711]

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