Nuclear Localization of Robo is Associated with Better Survival in Bladder Cancer
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The Slit-Robo pathway has shown to be altered in several malignant diseases. However, its role in bladder cancer is poorly understood. Therefore, we aimed to assess the tissue expression of Robo1 and Robo4 as well as their ligand Slit2 in different stages of bladder cancer to explore possible changes of Slit-Robo signalling during the progression of bladder cancer. Robo1, Robo4 and Slit2 gene expressions were analyzed in 92 frozen bladder cancer tissue samples by using reverse transcription quantitative real-time PCR. Immunohistochemical analyses were performed on 149 formalin-fixed and paraffin-embedded bladder cancer tissue samples. Results were correlated with the clinical and follow-up data by performing both univariable and multivariable analyses. Robo1 and Robo4 nuclear staining intensitiy was significantly higher in low stage and low grade bladder cancer. Elevated Robo1 nuclear staining was associated with better disease-specific survival (DSS) (p = 0.045). Similarly, stronger Robo4 nuclear staining tended to be associated with longer DSS (p = 0.061). We found higher Robo1 and Slit2 gene expression levels in advanced stages of bladder cancer (p = 0.007 and p < 0.001). High Slit2 gene expression was correlated with significantly shorter DSS (p < 0.005), while Robo1 and Robo4 gene expressions were not associated with patients’ prognosis. Our results demonstrate that the nuclear expression of Robo1 and Robo4 is associated with a favourable prognosis suggesting that its translocation into the nucleus represent a posttranslational regulation process which may exhibit an antitumor effect in bladder cancer.
KeywordsBladder Cancer Robo1 Robo4 Nuclear translocation Slit2 Prognosis Angiogenesis
This work was supported by the National Research, Development and Innovation Office – NKFIH / PD 115616. Tibor Szarvas was supported by János Bolyai Research Scholarship of the Hungarian Academy of Sciences.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 2.Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, Hinoue T, Laird PW, Hoadley KA, Akbani R, Castro MAA, Gibb EA, Kanchi RS, Gordenin DA, Shukla SA, Sanchez-Vega F, Hansel DE, Czerniak BA, Reuter VE, Su X, de Sa Carvalho B, Chagas VS, Mungall KL, Sadeghi S, Pedamallu CS, Lu Y, Klimczak LJ, Zhang J, Choo C, Ojesina AI, Bullman S, Leraas KM, Lichtenberg TM, Wu CJ, Schultz N, Getz G, Meyerson M, Mills GB, McConkey DJ, Weinstein JN, Kwiatkowski DJ, Lerner SP (2017) Comprehensive molecular characterization of muscle-invasive bladder Cancer. Cell 171(3):540–556.e525. https://doi.org/10.1016/j.cell.2017.09.007 CrossRefPubMedGoogle Scholar
- 7.Sundaresan V, Heppell-Parton A, Coleman N, Miozzo M, Sozzi G, Ball R, Cary N, Hasleton P, Fowler W, Rabbitts P (1995) Somatic genetic changes in lung cancer and precancerous lesions. Ann Oncol 6(Suppl 1):27–31 discussion 31-22Google Scholar
- 8.Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491(7424):399–405. https://doi.org/10.1038/nature11547 CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Zhou WJ, Geng ZH, Chi S, Zhang W, Niu XF, Lan SJ, Ma L, Yang X, Wang LJ, Ding YQ, Geng JG (2011) Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis. Cell Res 21(4):609–626. https://doi.org/10.1038/cr.2011.17 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Marlow R, Strickland P, Lee JS, Wu X, Pebenito M, Binnewies M, Le EK, Moran A, Macias H, Cardiff RD, Sukumar S, Hinck L (2008) SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium. Cancer Res 68(19):7819–7827. https://doi.org/10.1158/0008-5472.can-08-1357 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Schmid BC, Rezniczek GA, Fabjani G, Yoneda T, Leodolter S, Zeillinger R (2007) The neuronal guidance cue Slit2 induces targeted migration and may play a role in brain metastasis of breast cancer cells. Breast Cancer Res Treat 106(3):333–342. https://doi.org/10.1007/s10549-007-9504-0 CrossRefPubMedGoogle Scholar
- 20.Fujiwara M, Ghazizadeh M, Kawanami O (2006) Potential role of the Slit/Robo signal pathway in angiogenesis. Vasc Med (London, England) 11(2):115–121Google Scholar
- 21.Seki M, Watanabe A, Enomoto S, Kawamura T, Ito H, Kodama T, Hamakubo T, Aburatani H (2010) Human ROBO1 is cleaved by metalloproteinases and gamma-secretase and migrates to the nucleus in cancer cells. FEBS Lett 584(13):2909–2915. https://doi.org/10.1016/j.febslet.2010.05.009 CrossRefPubMedGoogle Scholar