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Low RKIP expression associates with poor prognosis in bladder cancer patients

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Abstract

Urothelial bladder cancer (UBC) is a heterogeneous type of disease. It is urgent to screen biomarkers of tumour aggressiveness in order to clarify the clinical behaviour and to personalize therapy in UBC patients. Raf kinase inhibitory protein (RKIP) is a metastasis suppressor, and its downregulation is associated with metastatic events in an increasing number of solid tumours. We evaluated the clinical and prognostic significance of RKIP expression in patients with high risk of progression UBC. Using immunohistochemistry, we determined RKIP expression levels in a series of 81 patients with high-grade pT1/pTis or muscle-invasive UBC. Staining of CD31 and D2-40 was used to assess blood and lymphatic vessels, in order to distinguish between blood and lymphatic vessel invasion (LVI). We found that 90 % of pT1/pTis tumours, 94 % of non-muscle invasive papillary tumours and 76 % of the cases without LVI occurrence expressed RKIP in >10 % of cells. In this group, we observed a subgroup of tumours (42 %) in which the tumour centre was significantly more intensely stained than the invasion front. This heterogeneous pattern was observed in 63 % of the cases with LVI. Low RKIP expression was associated with poorer 5-year disease-free and overall survival rates, and remained as an independent prognostic factor for disease-free survival. Loss of RKIP expression may be an important prognostic factor for patients with high risk of progression bladder cancer.

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References

  1. Kaufman DS, Shipley WU, Feldman AS (2009) Bladder cancer. Lancet 374:239–249

    Article  PubMed  CAS  Google Scholar 

  2. Sternberg CN, Donat SM, Bellmunt J et al (2007) Chemotherapy for bladder cancer: treatment guidelines for neoadjuvant chemotherapy, bladder preservation, adjuvant chemotherapy, and metastatic cancer. Urology 69(Suppl 1):62–79

    Article  PubMed  Google Scholar 

  3. Sternberg CN (2006) Muscle invasive and metastatic bladder cancer. Ann Oncol 17(Suppl 10):23–30

    Article  Google Scholar 

  4. Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26:3279–3290

    Article  PubMed  CAS  Google Scholar 

  5. Davies H, Bignell GR, Cox C et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  PubMed  CAS  Google Scholar 

  6. Stoehr R, Brinkmann A, Filbeck T et al (2004) No evidence for mutation of B-RAF in urothelial carcinomas of the bladder and upper urinary tract. Oncol Rep 11(Suppl 1):137–141

    PubMed  CAS  Google Scholar 

  7. Boulalas I, Zaravinos A, Delakas D, Spandidos DA (2009) Mutational analysis of the BRAF gene in transitional cell carcinoma of the bladder. Int J Biol Markers 24(Suppl 1):17–21

    PubMed  CAS  Google Scholar 

  8. Karlou M, Saetta AA, Korkolopoulou P et al (2009) Activation of extracellular regulated kinases (ERK1/2) predicts poor prognosis in urothelial bladder carcinoma and is not associated with B-Raf gene mutations. Pathology 41(Suppl 4):327–334

    Article  PubMed  CAS  Google Scholar 

  9. Zaravinos A, Chatziioannou M, Lambrou GI et al (2011) Implication of RAF and RKIP genes in urinary bladder cancer. Pathol Oncol Res 17(Suppl2): 181–190

    Google Scholar 

  10. Klysik J, Theroux SJ, Sedivy JM, Moffit JS, Boekelheide K (2008) Signaling crossroads: the function of Raf kinase inhibitory protein in cancer, the central nervous system and reproduction. Cell Signal 20:1–9

    Article  PubMed  CAS  Google Scholar 

  11. Hellmann J, Rommelspacher H, Mühlbauer E, Wernicke C (2010) Raf kinase inhibitor protein enhances neuronal differentiation in human SH-SY5Y cells. Dev Neurosci 32(1):33–46

    Article  PubMed  CAS  Google Scholar 

  12. Eves EM, Shapiro P, Naik K et al (2006) Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Mol Cell 23(4):561–574

    Article  PubMed  CAS  Google Scholar 

  13. Al-Mulla F, Bitar MS, Taqi Z, Rath O, Kolch W (2011) RAF kinase inhibitory protein (RKIP) modulates cell cycle kinetics and motility. Mol Biosyst 7(3):928–941

    Article  PubMed  CAS  Google Scholar 

  14. Yeung KC, Rose DW, Dhillon AS et al (2001) Raf kinase inhibitor protein interacts witw NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation. Mol Cell Biol 21:7207–7217

    Article  PubMed  CAS  Google Scholar 

  15. Kim SY, Park SG, Jung H et al (2011) RKIP downregulation induces the HBx-mediated Raf-1 mitochondrial translocation. J Microbiol Biotechnol 21(5):525–528

    Article  PubMed  CAS  Google Scholar 

  16. Baritaki S, Chapman A, Yeung K et al (2009) Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: pivotal roles of Snail repression and RKIP induction. Oncogene 28(40):3573–3485

    Article  PubMed  CAS  Google Scholar 

  17. Wu K, Bonavida B (2009) The activated NF-kappaB-Snail-RKIP circuitry in cancer regulates both the metastatic cascade and resistance to apoptosis by cytotoxic drugs. Crit Rev Immunol 29(3):241–254

    Article  PubMed  CAS  Google Scholar 

  18. Zhu S, Mc Henry KT, Lane WS, Fenteany G (2005) A chemical inhibitor reveals the role of Raf kinase inhibitor protein in cell migration. Chem Biol 12(9):981–991

    Article  PubMed  CAS  Google Scholar 

  19. Yeung K, Janosch P, McFerran B et al (2000) Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Mol Cell Biol 20(9):3079–3085

    Article  PubMed  CAS  Google Scholar 

  20. Tang H, Park S, Sun SC et al (2010) RKIP inhibits NF-kappaB in cancer cells by regulating upstream signaling components of the IkappaB kinase complex. FEBS Lett 584(4):662–668

    Article  PubMed  CAS  Google Scholar 

  21. Lorenz K, Lohse MJ, Quitterer U et al (2003) Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature 426:574–579

    Article  PubMed  CAS  Google Scholar 

  22. Al-Mulla F, Bitar MS, Al-Maghrebi M et al (2011) Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β. Cancer Res 71(4):1334–1343

    Article  PubMed  CAS  Google Scholar 

  23. Fu Z, Smith PC, Zhang L (2003) Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J Natl Cancer Inst 95:878–879

    Article  PubMed  CAS  Google Scholar 

  24. Hagan S, Al-Mulla F, Mallon E (2005) Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis. Clin Cancer Res 11:7392–7397

    Article  PubMed  CAS  Google Scholar 

  25. Al-Mulla F, Hagan S, Behbehani AI (2006) Raf kinase inhibitor protein expression in a survival analysis of colorectal cancer patients. J Clin Oncol 24:5672–5679

    Article  PubMed  CAS  Google Scholar 

  26. Schuierer MM, Bataille F, Hagan S, Kolch W, Bosserhoff AK (2004) Reduction of Raf kinase inhibitor protein expression is associated with increased Ras-extracellular signal-regulated kinase signaling in melanoma cell lines. Cancer Res 64:5186–5192

    Article  PubMed  CAS  Google Scholar 

  27. Afonso J, Santos LL, Amaro T, Lobo F, Longatto-Filho A (2009) The aggressiveness of urothelial carcinoma depends to a large extent on lymphovascular invasion—the prognostic contribution of related molecular markers. Histopathology 55:514–524

    Article  PubMed  Google Scholar 

  28. Amin MB, Srigley JR, Grignon DJ et al (2005) Urinary bladder cancer protocols and checklists. College of American Pathologists, Northfield

    Google Scholar 

  29. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (2010) AJCC cancer staging manual. Springer, New York

    Google Scholar 

  30. Mostofi CJ, Davis CJ, Sesterhenn IA (1999) World Health Organization, International Histological Classification of Tumours. Histological typing of urinary bladder tumours. Springer, Berlin

    Book  Google Scholar 

  31. Eble JN, Sauter G, Epstein JI, Sesterhenn IA (2004) World Health Organization Classification of Tumours. Pathology and genetics of tumours of the urinary system and male genital organ. IARC Press, Lyon

    Google Scholar 

  32. Martinho O, Gouveia A, Silva P et al (2009) Loss of RKIP expression is associated with poor survival in GISTs. Virchows Arch 455(Suppl 3):277–284

    Article  PubMed  CAS  Google Scholar 

  33. Martinho O, Faloppa CC, Neto CS et al (2012) Loss of RKIP expression during the carcinogenic evolution of endometrial cancer. J Clin Pathol 65(Suppl 2):122–128

    Article  PubMed  Google Scholar 

  34. Martinho O, Granja S, Jaraquemada T et al (2012) Downregulation of RKIP is associated with poor outcome and malignant progression in gliomas. PLoS One 7(1):e30769

    Article  PubMed  CAS  Google Scholar 

  35. Bevilacqua E, Frankenberger CA, Rosner MR (2012) RKIP suppresses breast cancer metastasis to the bone by regulating stroma-associated genes. Int J Breast Cancer 2012:124704

    PubMed  Google Scholar 

  36. Hao C, Wei S, Tong Z et al (2012) The effects of RKIP gene expression on the biological characteristics of human triple-negative breast cancer cells in vitro. Tumour Biol 33(Suppl 4):1159–1167

    Article  PubMed  CAS  Google Scholar 

  37. Xinzhou H, Ning Y, Ou W et al (2011) RKIP inhibits the migration and invasion of human prostate cancer PC-3 M cells through regulation of extracellular matrix. Mol Biol (Mosk) 45(Suppl 6):1004–1011

    CAS  Google Scholar 

  38. Beshir AB, Ren G, Magpusao AN et al (2010) Raf kinase inhibitor protein suppresses nuclear factor-κB-dependent cancer cell invasion through negative regulation of matrix metalloproteinase expression. Cancer Lett 299(Suppl 2):137–149

    Article  PubMed  CAS  Google Scholar 

  39. Beach S, Tang H, Park S et al (2008) Snail is a repressor of RKIP transcription in metastatic prostate cancer cells. Oncogene 27(Suppl 15):2243–2248

    Article  PubMed  CAS  Google Scholar 

  40. Thuault S, Valcourt U, Petersen M et al (2006) Transforming growth factor-beta employs HMGA2 to elicit epithelial–mesenchymal transition. J Cell Biol 174(2):175–183

    Article  PubMed  CAS  Google Scholar 

  41. Lee YS, Dutta A (2007) The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21(9):1025–1030

    Article  PubMed  CAS  Google Scholar 

  42. Dangi-Garimella S, Yun J, Eves EM et al (2009) Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO J 28(4):347–358

    Article  PubMed  CAS  Google Scholar 

  43. Yun J, Frankenberger CA, Kuo WL et al (2011) Signalling pathway for RKIP and Let-7 regulates and predicts metastatic breast cancer. EMBO J 30(21):4500–4514

    Article  PubMed  CAS  Google Scholar 

  44. Zhang L, Fu Z, Binkley C et al (2004) Raf kinase inhibitory protein inhibits beta-cell proliferation. Surgery 136:708–715

    Article  PubMed  Google Scholar 

  45. Li HZ, Wang Y, Gao Y et al (2008) Effects of raf kinase inhibitor protein expression on metastasis and progression of human epithelial ovarian cancer. Mol Cancer Res 6(Suppl 6):917–928

    Article  PubMed  CAS  Google Scholar 

  46. Wang J, Yang YH, Wang AQ (2010) Immunohistochemical detection of the Raf kinase inhibitor protein in nonneoplastic gastric tissue and gastric cancer tissue. Med Oncol 27(Suppl 2):219–223

    Article  PubMed  Google Scholar 

  47. Lee HC, Tian B, Sedivy JM, Wands JR, Kim M (2006) Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Gastroenterology 131(Suppl 4):1208–1217

    Article  PubMed  CAS  Google Scholar 

  48. Hu CJ, Zhou L, Zhang J, Huang C, Zhang GM (2011) Immunohistochemical detection of Raf kinase inhibitor protein in normal cervical tissue and cervical cancer tissue. J Int Med Res 39(Suppl 1):229–237

    PubMed  CAS  Google Scholar 

  49. Kim HS, Won KY, Kim GY et al (2012) Reduced expression of Raf-1 kinase inhibitory protein predicts regional lymph node metastasis and shorter survival in esophageal squamous cell carcinoma. Pathol Res Pract 208(Suppl 5):292–299

    Article  PubMed  CAS  Google Scholar 

  50. Kim HS, Lee SH, Won KY (2012) Expression of Raf-1 kinase inhibitory protein in carcinoma of the ampulla of Vater. Virchows Arch 460(Suppl 1):61–68

    Article  PubMed  CAS  Google Scholar 

  51. Fu Z, Kitagawa Y, Shen R et al (2006) Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer. Prostate 66:248–256

    Article  PubMed  CAS  Google Scholar 

  52. Chatterjee D, Sabo E, Tavares R, Resnick MB (2008) Inverse association between Raf Kinase Inhibitory Protein and signal transducers and activators of transcription 3 expression in gastric adenocarcinoma patients: implications for clinical outcome. Clin Cancer Res 14(Suppl 10):2994–3001

    Article  PubMed  CAS  Google Scholar 

  53. Gao C, Pang L, Ren C, Ma T (2012) Prognostic value of raf kinase inhibitor protein in esophageal squamous cell carcinoma. Pathol Oncol Res 18(Suppl 2):471–477

    Article  PubMed  CAS  Google Scholar 

  54. Kim HS, Kim GY, Lim SJ, Kim YW (2010) Loss of Raf-1 kinase inhibitory protein in pancreatic ductal adenocarcinoma. Pathology 42(Suppl 7):655–660

    Article  PubMed  Google Scholar 

  55. Kim HS, Kim GY, Lim SJ, Park YK, Kim YW (2010) Reduced expression of Raf-1 kinase inhibitory protein is a significant prognostic marker in patients with gallbladder carcinoma. Hum Pathol 41(Suppl 11):1609–1616

    Article  PubMed  CAS  Google Scholar 

  56. Chatterjee D, Bai Y, Wang Z et al (2004) RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis. J Biol Chem 279(Suppl 17):17515–17523

    Article  PubMed  CAS  Google Scholar 

  57. Ruan L, Wang GL, Yi H, Chen Y et al (2010) Raf kinase inhibitor protein correlates with sensitivity of nasopharyngeal carcinoma to radiotherapy. J Cell Biochem 110(Suppl 4):975–981

    Article  PubMed  CAS  Google Scholar 

  58. Woods Ignatoski KM, Grewal NK, Markwart SM et al (2008) Loss of Raf kinase inhibitory protein induces radioresistance in prostate cancer. Int J Radiat Oncol Biol Phys 72(Suppl 1):153–160

    Article  PubMed  CAS  Google Scholar 

  59. Al-Mulla F, Hagan S, Al-Ali W (2008) Raf kinase inhibitor protein: mechanism of loss of expression and association with genomic instability. J Clin Pathol 61(Suppl 4):524–529

    Article  PubMed  CAS  Google Scholar 

  60. Minoo P, Baker K, Goswami R (2006) Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis. Gut 55(Suppl 10):1467–1474

    Article  PubMed  CAS  Google Scholar 

  61. Ren G, Baritaki S, Marathe H et al (2012) Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res 72(12):3091–3104

    Article  PubMed  CAS  Google Scholar 

  62. Al-Mulla F, Bitar MS, Feng J, Park S, Yeung KC (2012) A new model for raf kinase inhibitory protein induced chemotherapeutic resistance. PLoS One 7(1):e29532

    Article  PubMed  CAS  Google Scholar 

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Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Life and Health Sciences Research Institute–ICVS, University of Minho, Braga, Portugal

    Julieta Afonso, Adhemar Longatto-Filho, Olga Martinho & Rui M. Reis

  2. ICVS/3B’s–PT Government Associate Laboratory, Braga, Portugal

    Julieta Afonso, Adhemar Longatto-Filho, Olga Martinho & Rui M. Reis

  3. Laboratory of Medical Investigation (LIM 14), Faculty of Medicine, São Paulo State University, São Paulo, Brazil

    Adhemar Longatto-Filho

  4. Department of Urology, Portuguese Institute of Oncology–IPO, Porto, Portugal

    Francisco Lobo

  5. Experimental Pathology and Therapeutics Research Center, Portuguese Institute of Oncology–IPO, Porto, Portugal

    Teresina Amaro

  6. Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil

    Rui M. Reis

  7. Department of Surgical Oncology, Portuguese Institute of Oncology (IPO), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

    Lúcio L. Santos

  8. University Fernando Pessoa–UFP, Porto, Portugal

    Lúcio L. Santos

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  1. Julieta Afonso
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  2. Adhemar Longatto-Filho
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  3. Olga Martinho
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  4. Francisco Lobo
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Correspondence to Lúcio L. Santos.

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Afonso, J., Longatto-Filho, A., Martinho, O. et al. Low RKIP expression associates with poor prognosis in bladder cancer patients. Virchows Arch 462, 445–453 (2013). https://doi.org/10.1007/s00428-013-1388-2

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  • DOI: https://doi.org/10.1007/s00428-013-1388-2

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