open access

Vol 58, No 2 (2020)
Original paper
Submitted: 2020-03-12
Accepted: 2020-06-22
Published online: 2020-06-30
Get Citation

Downregulation of Polo-like kinase-1 (PLK-1) expression is associated with poor clinical outcome in uveal melanoma patients

Tomasz Berus1, Anna Markiewicz2, Katarzyna Kobylinska3, Przemyslaw Biecek3, Jolanta Orlowska-Heitzman4, Bozena Romanowska-Dixon2, Piotr Donizy5
·
Pubmed: 32602935
·
Folia Histochem Cytobiol 2020;58(2):108-116.
Affiliations
  1. Department of Ophthalmology, 4th Military Clinical Hospital with Polyclinic, Weigla 5, 50-981 Wroclaw, Poland
  2. Department of Ophthalmology and Ocular Oncology, the Jagiellonian University, Medical College, Kopernika 38, 31-501 Krakow, Poland
  3. Faculty of Mathematics, Informatics and Mechanics University of Warsaw, Warsaw, Poland
  4. Department of Pathomorphology, the Jagiellonian University, Medical College, Grzegorzecka 16, 31-531 Krakow, Poland
  5. Department of Pathomorphology and Oncological Cytology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland

open access

Vol 58, No 2 (2020)
ORIGINAL PAPERS
Submitted: 2020-03-12
Accepted: 2020-06-22
Published online: 2020-06-30

Abstract

Introduction. Uveal melanoma (UM) is the most common primary eye tumour in adults. Distant metastases are seen in 50% of cases regardless of treatment, which contributes to high mortality rates. Polo-like kinase-1 (PLK-1) is a protein regulator of mitotic entry and cytokinesis. Increased PLK-1 expression has been shown in different tumours, which makes its inhibition a potential treatment target. To date, no study has been published to discuss the prognostic role of PLK-1 expression in patients with uveal melanoma. Material and methods. We assessed by immunohistochemistry PLK-1 expression in uveal melanoma cells collected in 158 patients treated by primary enucleation. We determined the correlation between PLK-1 levels evaluated by the immunoreactivity scale (IRS) method and detailed clinical as well as histological parameters. Additionally, we determined the association between PLK-1 expression levels and long-term prognosis. Results. Elevated PLK-1 expression in tumour cells, defined as IRS > 2, was observed in 70% (111/158) of cases, whereas low expression or no expression was seen in the remaining 30% (47/158) of patients. There was a significant correlation between low PLK-1 expression and a higher clinical tumour stage (pT, p = 0.04) as well as a higher AJCC prognostic stage group (p = 0.037). We observed an inverse correlation between PLK-1 expression and tumour cell pigment content (p = 0.0019). There was no correlation between PLK-1 expression and other histological parameters such as mitotic rate or histological subtype. The Kaplan-Meier’s analysis demonstrated that low PLK-1 expression was associated with significantly reduced overall survival (p = 0.0058). A similar trend, albeit not significant, was observed for disease-free survival (p = 0.088). Conclusions. Downregulated PLK-1 expression is a negative prognostic factor in uveal melanoma. It warrants further, multicentre research on prognostic role of PLK-1 expression and possibility of PLK-1 inhibition in uveal melanoma.

Abstract

Introduction. Uveal melanoma (UM) is the most common primary eye tumour in adults. Distant metastases are seen in 50% of cases regardless of treatment, which contributes to high mortality rates. Polo-like kinase-1 (PLK-1) is a protein regulator of mitotic entry and cytokinesis. Increased PLK-1 expression has been shown in different tumours, which makes its inhibition a potential treatment target. To date, no study has been published to discuss the prognostic role of PLK-1 expression in patients with uveal melanoma. Material and methods. We assessed by immunohistochemistry PLK-1 expression in uveal melanoma cells collected in 158 patients treated by primary enucleation. We determined the correlation between PLK-1 levels evaluated by the immunoreactivity scale (IRS) method and detailed clinical as well as histological parameters. Additionally, we determined the association between PLK-1 expression levels and long-term prognosis. Results. Elevated PLK-1 expression in tumour cells, defined as IRS > 2, was observed in 70% (111/158) of cases, whereas low expression or no expression was seen in the remaining 30% (47/158) of patients. There was a significant correlation between low PLK-1 expression and a higher clinical tumour stage (pT, p = 0.04) as well as a higher AJCC prognostic stage group (p = 0.037). We observed an inverse correlation between PLK-1 expression and tumour cell pigment content (p = 0.0019). There was no correlation between PLK-1 expression and other histological parameters such as mitotic rate or histological subtype. The Kaplan-Meier’s analysis demonstrated that low PLK-1 expression was associated with significantly reduced overall survival (p = 0.0058). A similar trend, albeit not significant, was observed for disease-free survival (p = 0.088). Conclusions. Downregulated PLK-1 expression is a negative prognostic factor in uveal melanoma. It warrants further, multicentre research on prognostic role of PLK-1 expression and possibility of PLK-1 inhibition in uveal melanoma.

Get Citation

Keywords

uveal melanoma; polo-like kinase-1; prognostic factor; IHC

About this article
Title

Downregulation of Polo-like kinase-1 (PLK-1) expression is associated with poor clinical outcome in uveal melanoma patients

Journal

Folia Histochemica et Cytobiologica

Issue

Vol 58, No 2 (2020)

Article type

Original paper

Pages

108-116

Published online

2020-06-30

Page views

1366

Article views/downloads

795

DOI

10.5603/FHC.a2020.0017

Pubmed

32602935

Bibliographic record

Folia Histochem Cytobiol 2020;58(2):108-116.

Keywords

uveal melanoma
polo-like kinase-1
prognostic factor
IHC

Authors

Tomasz Berus
Anna Markiewicz
Katarzyna Kobylinska
Przemyslaw Biecek
Jolanta Orlowska-Heitzman
Bozena Romanowska-Dixon
Piotr Donizy

References (62)
  1. Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology. 2011; 118(9): 1881–1885.
  2. Berus T, Halon A, Markiewicz A, et al. Clinical, Histopathological and Cytogenetic Prognosticators in Uveal Melanoma - A Comprehensive Review. Anticancer Res. 2017; 37(12): 6541–6549.
  3. Rantala ES, Hernberg M, Kivelä TT. Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis. Melanoma Res. 2019; 29(6): 561–568.
  4. Elia AEH, Rellos P, Haire LF, et al. The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain. Cell. 2003; 115(1): 83–95.
  5. Archambault V, Lépine G, Kachaner D. Understanding the Polo Kinase machine. Oncogene. 2015; 34(37): 4799–4807.
  6. Combes G, Alharbi I, Braga LG, et al. Playing polo during mitosis: PLK1 takes the lead. Oncogene. 2017; 36(34): 4819–4827.
  7. Petronczki M, Lénárt P, Peters JM. Polo on the Rise-from Mitotic Entry to Cytokinesis with Plk1. Dev Cell. 2008; 14(5): 646–659.
  8. Lénárt P, Petronczki M, Steegmaier M, et al. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol. 2007; 17(4): 304–315.
  9. Barr FA, Silljé HHW, Nigg EA. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol. 2004; 5(6): 429–440.
  10. Liu XS, Song B, Liu X. The substrates of Plk1, beyond the functions in mitosis. Protein Cell. 2010; 1(11): 999–1010.
  11. Wolf G, Hildenbrand R, Schwar C, et al. Polo-like kinase: a novel marker of proliferation: Correlation with estrogen-receptor expression in human breast cancer. Pathology - Research and Practice. 2000; 196(11): 753–759.
  12. Donizy P, Halon A, Surowiak P, et al. Augmented expression of Polo-like kinase 1 is a strong predictor of shorter cancer-specific overall survival in early stage breast cancer at 15-year follow-up. Oncol Lett. 2016; 12(3): 1667–1674.
  13. Tokumitsu Y, Mori M, Tanaka S, et al. Prognostic significance of polo-like kinase expression in esophageal carcinoma. Int J Oncol. 1999; 15(4): 687–692.
  14. Wolf G, Elez R, Doermer A, et al. Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene. 1997; 14(5): 543–549.
  15. Takai N, Miyazaki T, Fujisawa K, et al. Expression of polo-like kinase in ovarian cancer is associated with histological grade and clinical stage. Cancer Lett. 2001; 164(1): 41–49.
  16. Macmillan JC, Hudson JW, Bull S, et al. Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer. Ann Surg Oncol. 2001; 8(9): 729–740.
  17. Cheng MW, Wang BC, Weng ZQ, et al. Clinicopathological significance of Polo-like kinase 1 (PLK1) expression in human malignant glioma. Acta Histochem. 2012; 114(5): 503–509.
  18. Lin P, Wen DY, Dang YW, et al. Comprehensive and Integrative Analysis Reveals the Diagnostic, Clinicopathological and Prognostic Significance of Polo-Like Kinase 1 in Hepatocellular Carcinoma. Cell Physiol Biochem. 2018; 47(3): 925–947.
  19. Kneisel L, Strebhardt K, Bernd A, et al. Expression of polo-like kinase (PLK1) in thin melanomas: a novel marker of metastatic disease. J Cutan Pathol. 2002; 29(6): 354–358.
  20. Strebhardt, K. Prognostic Value of Pololike Kinase Expression in Melanomas. JAMA: The Journal of the American Medical Association. 2000; 283(4): 479–480.
  21. Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 2017; 17(2): 93–115.
  22. Bailey FP, Clarke K, Kalirai H, et al. Kinome-wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics. Pigment Cell Melanoma Res. 2018; 31(2): 253–266.
  23. Grossniklaus HE, Finger PT, Harbour JW, et al. Protocol for the Examination of Specimens From Patients With Uveal Melanoma, https://documents.cap.org/protocols/cp-uveal-melanoma-17protocol-4000.pdf (2017, accessed 12 March 2020).
  24. Remmele W, Stegner HE. [Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue]. Pathologe. 1987; 8(3): 138–140.
  25. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, https://www.r-project.org/ (2019, accessed 12 March 2020).
  26. Kassambara A, Kosinski M, Biecek P. survminer: Drawing Survival Curves using ‘ggplot2’. R package version 0.4.6., https://cran.r-project.org/package=survminer (2019, accessed 12 March 2020).
  27. Strebhardt K. Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy. Nat Rev Drug Discov. 2010; 9(8): 643–660.
  28. Eckerdt F, Yuan J, Strebhardt K. Polo-like kinases and oncogenesis. Oncogene. 2005; 24(2): 267–276.
  29. Takai N, Hamanaka R, Yoshimatsu J, et al. Polo-like kinases (Plks) and cancer. Oncogene. 2005; 24(2): 287–291.
  30. Weng Ng WT, Shin JS, Roberts TL, et al. Molecular interactions of polo-like kinase 1 in human cancers. J Clin Pathol. 2016; 69(7): 557–562.
  31. Liu XS, Li H, Song B, et al. Polo-like kinase 1 phosphorylation of G2 and S-phase-expressed 1 protein is essential for p53 inactivation during G2 checkpoint recovery. EMBO Rep. 2010; 11(8): 626–632.
  32. Yang X, Li H, Zhou Z, et al. Plk1-mediated phosphorylation of Topors regulates p53 stability. J Biol Chem. 2009; 284(28): 18588–18592.
  33. Chen J, Dai Gu, Wang YQ, et al. Polo-like kinase 1 regulates mitotic arrest after UV irradiation through dephosphorylation of p53 and inducing p53 degradation. FEBS Lett. 2006; 580(15): 3624–3630.
  34. Dias SS, Hogan C, Ochocka AM, et al. Polo-like kinase-1 phosphorylates MDM2 at Ser260 and stimulates MDM2-mediated p53 turnover. FEBS Lett. 2009; 583(22): 3543–3548.
  35. Ando K, Ozaki T, Yamamoto H, et al. Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation. J Biol Chem. 2004; 279(24): 25549–25561.
  36. McKenzie L, King S, Marcar L, et al. p53-dependent repression of polo-like kinase-1 (PLK1). Cell Cycle. 2010; 9(20): 4200–4212.
  37. Liu X, Erikson RL. Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci U S A. 2003; 100(10): 5789–5794.
  38. Liu X, Lei M, Erikson RL. Normal cells, but not cancer cells, survive severe Plk1 depletion. Mol Cell Biol. 2006; 26(6): 2093–2108.
  39. Guan R, Tapang P, Leverson JD, et al. Small interfering RNA-mediated Polo-like kinase 1 depletion preferentially reduces the survival of p53-defective, oncogenic transformed cells and inhibits tumor growth in animals. Cancer Res. 2005; 65(7): 2698–2704.
  40. Ren Y, Bi C, Zhao X, et al. PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas. J Clin Invest. 2018; 128(12): 5517–5530.
  41. Xiao D, Yue M, Su H, et al. Polo-like Kinase-1 Regulates Myc Stabilization and Activates a Feedforward Circuit Promoting Tumor Cell Survival. Mol Cell. 2016; 64(3): 493–506.
  42. Choi BH, Pagano M, Dai W. Plk1 protein phosphorylates phosphatase and tensin homolog (PTEN) and regulates its mitotic activity during the cell cycle. J Biol Chem. 2014; 289(20): 14066–14074.
  43. Cárcer Gde. The Mitotic Cancer Target Polo-Like Kinase 1: Oncogene or Tumor Suppressor? Genes. 2019; 10(3): 208.
  44. Boehringer Ingelheim’s investigational volasertib receives FDA Breakthrough Therapy designation, https://www.boehringer-ingelheim.us/press-release/boehringer-ingelheims-investigational-volasertib-receives-fda-breakthrough-therapy (accessed 1 February 2020).
  45. Volasertib in Combination With Low-dose Cytarabine in Patients Aged 65 Years and Above With Previously Untreated Acute Myeloid Leukaemia, Who Are Ineligible for Intensive Remission Induction Therapy (POLO-AML-2), https://clinicaltrials.gov/ct2/show/NCT01721876?term=polo-aml-2&rank=1 (accessed 1 February 2020).
  46. Van den Bossche J, Lardon F, Deschoolmeester V, et al. Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor. Med Res Rev. 2016; 36(4): 749–786.
  47. Gutteridge RE, Ndiaye MA, Liu X, et al. Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics. Mol Cancer Ther. 2016; 15(7): 1427–1435.
  48. Lu LY, Yu X. The balance of Polo-like kinase 1 in tumorigenesis. Cell Div. 2009; 4: 4.
  49. Lu LY, Wood JL, Minter-Dykhouse K, et al. Polo-like kinase 1 is essential for early embryonic development and tumor suppression. Mol Cell Biol. 2008; 28(22): 6870–6876.
  50. Wierer M, Verde G, Pisano P, et al. PLK1 signaling in breast cancer cells cooperates with estrogen receptor-dependent gene transcription. Cell Rep. 2013; 3(6): 2021–2032.
  51. de Cárcer G, Venkateswaran SV, Salgueiro L, et al. Plk1 overexpression induces chromosomal instability and suppresses tumor development. Nat Commun. 2018; 9(1): 3012.
  52. Raab M, Sanhaji M, Matthess Y, et al. PLK1 has tumor-suppressive potential in APC-truncated colon cancer cells. Nat Commun. 2018; 9(1): 1106.
  53. The Cancer Genome Atlas Program, https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga (accessed 1 February 2020).
  54. Györffy B, Lanczky A, Eklund AC, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010; 123(3): 725–731.
  55. The Kaplan Meier plotter, www.kmplot.com (accessed 1 February 2020).
  56. Jalili A, Moser A, Pashenkov M, et al. Polo-like kinase 1 is a potential therapeutic target in human melanoma. J Invest Dermatol. 2011; 131(9): 1886–1895.
  57. Zhang Z, Zhang G, Gao Z, et al. Comprehensive analysis of differentially expressed genes associated with PLK1 in bladder cancer. BMC Cancer. 2017; 17(1): 861.
  58. Chen J, Wu F, Shi Yu, et al. Identification of key candidate genes involved in melanoma metastasis. Mol Med Rep. 2019; 20(2): 903–914.
  59. Schmit TL, Zhong W, Setaluri V, et al. Targeted depletion of Polo-like kinase (Plk) 1 through lentiviral shRNA or a small-molecule inhibitor causes mitotic catastrophe and induction of apoptosis in human melanoma cells. J Invest Dermatol. 2009; 129(12): 2843–2853.
  60. Posch C, Cholewa BD, Vujic I, et al. Combined Inhibition of MEK and Plk1 Has Synergistic Antitumor Activity in NRAS Mutant Melanoma. J Invest Dermatol. 2015; 135(10): 2475–2483.
  61. Chen HY, Villanueva J. Playing Polo-Like Kinase in NRAS-Mutant Melanoma. J Invest Dermatol. 2015; 135(10): 2352–2355.
  62. Basile MS, Mazzon E, Fagone P, et al. Immunobiology of Uveal Melanoma: State of the Art and Therapeutic Targets. Front Oncol. 2019; 9: 1145.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By VM Media Group sp z o.o., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl