Ukr.Biochem.J. 2019; Volume 91, Issue 6, Nov-Dec, pp. 15-26


Analysis of Aurora kinases genes expression points on their distinct roles in prostate cancer development

O. Mankovska1, G. Gerashchenko1, E. Rozenberg1, E. Stakhovsky2,
O. Kononenko2, Yu. Bondarenko3, V. Kashuba1,4

1Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv;
2National Cancer Institute, Ministry of Health of Ukraine, Kyiv;
3Institute of Urology National Academy of Medical Sciences of Ukraine, Kyiv;
4Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden;

Received: 28 May 2019; Accepted: 18 October 2019

Aurora kinases A and B play a crucial role in the regulation of mitosis, while Aurora C controls meiotic division. These proteins showed controversial behavior upon the development of epithelial tumors. Our aim was to examine if there are any differences in expression of Aurora kinases genes in malignant and non-malignant tumors and non-tumor tissues; to compare their expression with clinical characteristics of patients and expression of other prostate cancer-associated genes. Quantitative RT-PCR was used to determine Aurora A-C genes expression in 33 prostate adenocarcinomas (T), paired conventionally normal tissues (N), and 17 ade­nomas (A). Relative expression values (RE) for genes studied were estimated using 2-ΔCt and 2-ΔΔCt method. The Kruskal-Wallis with correction on multiple comparisons, according to the Benjamini-Hochberg procedure with FDR = 0.2, Dunn-Bonferroni post hoc test and Spearman rank correlation analysis were used for statistical analysis. As turned out, RE values for AURKA were found to be significantly lower in samples of T group in comparison with A group. Moreover, significant up-regulation of AURKC expression levels were detected for T 3-4 stage compared to T 1-2 stage. RE values of AURKC in T group were positively correlated with the tumor stage, while AURKB RE demonstrated a negative correlation with the tumor stage. We also found significant correlations between AURK genes expression levels and prostate cancer-associated genes in T group. We suppose that all these data point to probable involvement of Aurora kinases’ genes in prostate carcinogenesis.

Keywords: , , , ,


  1. Tolkach Y, Kristiansen G. The Heterogeneity of Prostate Cancer: A Practical Approach. Pathobiology. 2018;85(1-2):108-116. PubMed, CrossRef
  2. Cancer Genome Atlas Research Network. The Molecular Taxonomy of Primary Prostate Cancer. Cell. 2015 Nov 5;163(4):1011-25. PubMed, PubMedCentral, CrossRef
  3. Jaratlerdsiri W, Chan EKF, Petersen DC, Yang C, Croucher PI, Bornman MSR, Sheth P, Hayes VM. Next generation mapping reveals novel large genomic rearrangements in prostate cancer. Oncotarget. 2017 Apr 4;8(14):23588-23602. PubMed, PubMedCentral, CrossRef
  4. Do TV, Hirst J, Hyter S, Roby KF, Godwin AK. Aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian carcinoma cells. Oncotarget. 2017 Jul 5;8(31):50376-50392. PubMed, PubMedCentral, CrossRef
  5. Kalsbeek D, Golsteyn RM. G2/M-Phase Checkpoint Adaptation and Micronuclei Formation as Mechanisms That Contribute to Genomic Instability in Human Cells. Int J Mol Sci. 2017 Nov 6;18(11). pii: E2344.  PubMed, PubMedCentral, CrossRef
  6. Tang A, Gao K, Chu L, Zhang R, Yang J, Zheng J. Aurora kinases: novel therapy targets in cancers. Oncotarget. 2017 Apr 4;8(14):23937-23954. PubMed, PubMedCentral, CrossRef
  7. Lindon C, Grant R, Min M. Ubiquitin-Mediated Degradation of Aurora Kinases. Front Oncol. 2016 Jan 18;5:307. PubMed, PubMedCentral, CrossRef
  8. Fu J, Bian M, Jiang Q, Zhang C. Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res. 2007 Jan;5(1):1-10. PubMed, CrossRef
  9. Lehman NL, O’Donnell JP, Whiteley LJ, Stapp RT, Lehman TD, Roszka KM, Schultz LR, Williams CJ, Mikkelsen T, Brown SL, Ecsedy JA, Poisson LM. Aurora A is differentially expressed in gliomas, is associated with patient survival in glioblastoma and is a potential chemotherapeutic target in gliomas. Cell Cycle. 2012 Feb 1;11(3):489-502. PubMed, PubMedCentral, CrossRef
  10. Kamada K, Yamada Y, Hirao T, Fujimoto H, Takahama Y, Ueno M, Takayama T, Naito A, Hirao S, Nakajima Y. Amplification/overexpression of Aurora-A in human gastric carcinoma: potential role in differentiated type gastric carcinogenesis. Oncol Rep. 2004 Sep;12(3):593-9. PubMed, CrossRef
  11. Krenn V, Musacchio A. The Aurora B Kinase in Chromosome Bi-Orientation and Spindle Checkpoint Signaling. Front Oncol. 2015 Oct 16;5:225.
    PubMed, PubMedCentral, CrossRef
  12. Shrestha RL, Conti D, Tamura N, Braun D, Ramalingam RA, Cieslinski K, Ries J, Draviam VM. Aurora-B kinase pathway controls the lateral to end-on conversion of kinetochore-microtubule attachments in human cells. Nat Commun. 2017 Jul 28;8(1):150. PubMed, PubMedCentral, CrossRef
  13. Chieffi P, Cozzolino L, Kisslinger A, Libertini S, Staibano S, Mansueto G, De Rosa G, Villacci A, Vitale M, Linardopoulos S, Portella G, Tramontano D. Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation. Prostate. 2006 Feb 15;66(3):326-33. PubMed, CrossRef
  14. Kimura M, Matsuda Y, Yoshioka T, Okano Y. Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J Biol Chem. 1999 Mar 12;274(11):7334-40. PubMed, CrossRef
  15. Yan X, Cao L, Li Q, Wu Y, Zhang H, Saiyin H, Liu X, Zhang X, Shi Q, Yu L. Aurora C is directly associated with Survivin and required for cytokinesis. Genes Cells. 2005 Jun;10(6):617-26. PubMed, CrossRef
  16. Quartuccio SM, Schindler K. Functions of Aurora kinase C in meiosis and cancer. Front Cell Dev Biol. 2015 Aug 20;3:50. PubMed, PubMedCentral, CrossRef
  17. Khan J, Ezan F, Crémet JY, Fautrel A, Gilot D, Lambert M, Benaud C, Troadec MB, Prigent C. Overexpression of active Aurora-C kinase results in cell transformation and tumour formation. PLoS One. 2011;6(10):e26512.  PubMed, PubMedCentral, CrossRef
  18. Nna E, Madukwe J, Egbujo E, Obiorah C, Okolie C, Echejoh G, Yahaya A, Adisa J, Uzoma I. Gene expression of Aurora kinases in prostate cancer and nodular hyperplasia tissues. Med Princ Pract. 2013;22(2):138-43. PubMed, PubMedCentral, CrossRef
  19. Lee EC, Frolov A, Li R, Ayala G, Greenberg NM.  Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res. 2006 May 15;66(10):4996-5002. PubMed, CrossRef
  20. Mevs LV, Gerashchenko GV, Rosenberg EE, Pikul MV, Marynychenko MV, Gryzodub OP, Vozianov SO, Stakhovsky EA, Kashuba VI. Detection of prostate specific ETS fusion transcripts in cancer samples. Biopolym Cell. 2017;33(4):256-67. CrossRef
  21. Gerashchenko GV, Mankovska OS, Dmitriev AA, Mevs LV, Rosenberg EE, Pikul MV, Marynychenko MV, Gryzodub OP, Stakhovsky EO, Kashuba VI. Expression of epithelial-mesenchymal transition-related genes in prostate tumours. Biopolym Cell. 2017;33(5):335-355. CrossRef
  22. Gerashchenko GV, Mevs LV, Chashchina LI, Pikul MV, Gryzodub OP, Stakhovsky EO, Kashuba VI. Expression of steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion. Exp Oncol. 2018 Jun;40(2):101-108. PubMed, CrossRef
  23. Baldini E, Arlot-Bonnemains Y, Sorrenti S, Mian C, Pelizzo MR, De Antoni E, Palermo S, Morrone S, Barollo S, Nesca A, Moretti CG, D’Armiento M, Ulisse S. Aurora kinases are expressed in medullary thyroid carcinoma (MTC) and their inhibition suppresses in vitro growth and tumorigenicity of the MTC derived cell line TT. BMC Cancer. 2011 Sep 26;11:411. PubMed, PubMedCentral, CrossRef
  24. Shoag J, Barbieri CE. Clinical variability and molecular heterogeneity in prostate cancer. Asian J Androl. 2016 Jul-Aug;18(4):543-8. PubMed, PubMedCentral, CrossRef
  25. Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell. 2010 Jun 15;18(6):884-901. PubMed, PubMedCentral, CrossRef
  26. Aran D, Camarda R, Odegaard J, Paik H, Oskotsky B, Krings G, Goga A, Sirota M, Butte AJ. Comprehensive analysis of normal adjacent to tumor transcriptomes. Nat Commun. 2017 Oct 20;8(1):1077. PubMed, PubMedCentral, CrossRef
  27. Briassouli P, Chan F, Savage K, Reis-Filho JS, Linardopoulos S. Aurora-A regulation of nuclear factor-kappaB signaling by phosphorylation of IkappaBalpha. Cancer Res. 2007 Feb 15;67(4):1689-95. PubMed, CrossRef
  28. Willems E, Dedobbeleer M, Digregorio M, Lombard A, Lumapat PN, Rogister B.  The functional diversity of Aurora kinases: a comprehensive review.  Cell Div. 2018 Sep 19;13:7. PubMed, PubMedCentral, CrossRef
  29. Senft D, Qi J, Ronai ZA. Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer. 2018 Feb;18(2):69-88. PubMed, PubMedCentral, CrossRef
  30. Shu SK, Liu Q, Coppola D, Cheng JQ. Phosphorylation and activation of androgen receptor by Aurora-A. J Biol Chem. 2010 Oct 22;285(43):33045-53.  PubMed, PubMedCentral, CrossRef
  31. Jones D, Noble M, Wedge SR, Robson CN, Gaughan L. Aurora A regulates expression of AR-V7 in models of castrate resistant prostate cancer. Sci Rep. 2017 Feb 16;7:40957. PubMed, PubMedCentral, CrossRef
  32. Suárez-Causado A, Caballero-Díaz D, Bertrán E, Roncero C, Addante A, García-Álvaro M, Fernández M, Herrera B, Porras A, Fabregat I, Sánchez A. HGF/c-Met signaling promotes liver progenitor cell migration and invasion by an epithelial-mesenchymal transition-independent, phosphatidyl inositol-3 kinase-dependent pathway in an in vitro model. Biochim Biophys Acta. 2015 Oct;1853(10 Pt A):2453-63.  PubMed, CrossRef
  33. Wang LH, Xiang J, Yan M, Zhang Y, Zhao Y, Yue CF, Xu J, Zheng FM, Chen JN, Kang Z, Chen TS, Xing D, Liu Q. The mitotic kinase Aurora-A induces mammary cell migration and breast cancer metastasis by activating the Cofilin-F-actin pathway. Cancer Res. 2010 Nov 15;70(22):9118-28.  PubMed, CrossRef
  34. Ding L, Zhang Z, Xu Y, Zhang Y. Comparative study of Her-2, p53, Ki-67 expression and clinicopathological characteristics of breast cancer in a cohort of northern China female patients. Bioengineered. 2017 Jul 4;8(4):383-392.  PubMed, PubMedCentral, CrossRef
  35. Tan PY, Chang CW, Chng KR, Wansa KD, Sung WK, Cheung E. Integration of regulatory networks by NKX3-1 promotes androgen-dependent prostate cancer survival. Mol Cell Biol. 2012 Jan;32(2):399-414. PubMed, PubMedCentral, CrossRef
  36. Decker J, Jain G, Kießling T, Sander P, Rid M,  Barth TTF, Möller P, Cronauer MV, Marienfeld RB. Loss of the Tumor Suppressor NKX3.1 in Prostate Cancer Cells is Induced by Prostatitis Related Mitogens. J Clin Exp Oncol. 2016;5:3.  CrossRef
  37. den Hollander J, Rimpi S, Doherty JR, Rudelius M, Buck A, Hoellein A, Kremer M, Graf N, Scheerer M, Hall MA, Goga A, von Bubnoff N, Duyster J, Peschel C, Cleveland JL, Nilsson JA, Keller U. Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood. 2010 Sep 2;116(9):1498-505. PubMed, PubMedCentral, CrossRef
  38. Hendrickson WK, Flavin R, Kasperzyk JL, Fiorentino M, Fang F, Lis R, Fiore C, Penney KL, Ma J, Kantoff PW, Stampfer MJ, Loda M, Mucci LA, Giovannucci E. Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. J Clin Oncol. 2011 Jun 10;29(17):2378-85. PubMed, PubMedCentral, CrossRef
  39. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD, Nelson PS. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008 Jun 1;68(11):4447-54. PubMed, PubMedCentral, CrossRef
  40. Kmeťová Sivoňová M, Jurečeková J, Tatarková Z, Kaplán P, Lichardusová L, Hatok J. The role of CYP17A1 in prostate cancer development: structure, function, mechanism of action, genetic variations and its inhibition. Gen Physiol Biophys. 2017 Dec;36(5):487-499.  PubMed, CrossRef
  41. Heidegger I, Kern J, Ofer P, Klocker H, Massoner P. Oncogenic functions of IGF1R and INSR in prostate cancer include enhanced tumor growth, cell migration and angiogenesis. Oncotarget. 2014 May 15;5(9):2723-35. PubMed, PubMed, CrossRef
  42. Weinstein D, Sarfstein R, Laron Z, Werner H. Insulin receptor compensates for IGF1R inhibition and directly induces mitogenic activity in prostate cancer cells. Endocr Connect. 2014 Jan 28;3(1):24-35.  PubMed, PubMedCentral, CrossRef
  43. McFarlane RJ, Wakeman JA. Meiosis-like Functions in Oncogenesis: A New View of Cancer. Cancer Res. 2017 Nov 1;77(21):5712-5716. PubMed, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.