Skip to main content

Advertisement

Log in

Reduced expression of Slit2 in renal cell carcinoma

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Slit2, initially identified as an important axon guidance molecule in the nervous system, was suggested to be involved in multiple cellular processes. Recently, Slit2 was reported to function as a potential tumor suppressor in diverse tumors. In this study, we systematically analyzed the expression level of Slit2 in renal cell carcinoma. Compared to paired adjacent non-malignant tissues, both Slit2 mRNA and protein expression were significantly down-regulated in renal cell carcinoma (RCC). Methylation-specific PCR showed that Slit2 promoter was methylated in two renal carcinoma cell lines. Pharmacologic demethylation dramatically induced Slit2 expression in cancer cell lines with weak expression of Slit2. Besides, bisulfite genomic sequencing confirmed that dense methylation existed in Slit2 promoter. Furthermore, in paired RCC samples, Slit2 methylation was observed in 8 out of 38 patients (21.1 %), which was well correlated with the down-regulation of Slit2 in RCC. Therefore, Slit2 may also be a potential tumor suppressor in RCC, which is down-regulated in RCC partially due to promoter methylation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. de Ibanez Caceres I, Dulaimi E, Hoffman AM, Al-Saleem T, Uzzo RG, Cairns P. Identification of novel target genes by an epigenetic reactivation screen of renal cancer. Cancer Res. 2006;66(10):5021–8. doi:10.1158/0008-5472.CAN-05-3365.

    Article  Google Scholar 

  2. Onay H, Onay H, Pehlivan S, Koyuncuoglu M, Kirkali Z, Ozkinay F. Multigene methylation analysis of conventional renal cell carcinoma. Urol Int. 2009;83(1):107–12. doi:10.1159/000224878.

    Article  CAS  PubMed  Google Scholar 

  3. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7(1):85–90. doi:10.1038/ng0594-85.

    Article  CAS  PubMed  Google Scholar 

  4. Kikuyama M, Takeshima H, Kinoshita T, Okochi-Takada E, Wakabayashi M, Wakabayashi M, Akashi-Tanaka S, Akashi-Tanaka S, et al. Development of a novel approach, the epigenome-based outlier approach, to identify tumor-suppressor genes silenced by aberrant DNA methylation. Cancer Lett. 2012;322(2):204–12. doi:10.1016/j.canlet.2012.03.016.

    Article  CAS  PubMed  Google Scholar 

  5. Baldewijns MM, van Vlodrop IJ, Schouten LJ, Soetekouw PM, de Bruine AP, van Engeland M. Genetics and epigenetics of renal cell cancer. Biochim Biophys Acta. 2008;1785(2):133–55. doi:10.1016/j.bbcan.2007.12.002.

    CAS  PubMed  Google Scholar 

  6. Morris MR, Gentle D, Abdulrahman M, Clarke N, Brown M, Kishida T, et al. Functional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma. Br J Cancer. 2008;98(2):496–501. doi:10.1038/sj.bjc.6604180.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Hoffman AM, Cairns P. Epigenetics of kidney cancer and bladder cancer. Epigenomics. 2011;3(1):19–34. doi:10.2217/epi.10.64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Morris, Ricketts C, Gentle D, Abdulrahman M, Clarke N, Brown M, et al. Identification of candidate tumour suppressor genes frequently methylated in renal cell carcinoma. Oncogene. 2010;29(14):2104–17. doi:10.1038/onc.2009.493.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Sogabe Y, Suzuki H, Toyota M, Ogi K, Imai T, Nojima M, et al. Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma. Int J Oncol. 2008;32(6):1253–61.

    CAS  PubMed  Google Scholar 

  10. Kagara I, Enokida H, Kawakami K, Matsuda R, Toki K, Nishimura H, et al. CpG hypermethylation of the UCHL1 gene promoter is associated with pathogenesis and poor prognosis in renal cell carcinoma. J Urol. 2008;180(1):343–51. doi:10.1016/j.juro.2008.02.044.

    Article  CAS  PubMed  Google Scholar 

  11. Lv D, Zhao W, Dong D, Qian XP, Zhang Y, Tian XJ, et al. Genetic and epigenetic control of UNC5C expression in human renal cell carcinoma. Eur J Cancer. 2011;47(13):2068–76. doi:10.1016/j.ejca.2011.04.021.

    Article  CAS  PubMed  Google Scholar 

  12. Lu D, Dong D, Zhou Y, Lu M, Pang XW, Li Y, et al. The tumor-suppressive function of UNC5D and its repressed expression in renal cell carcinoma. Clin Cancer Res. 2013;19(11):2883–92. doi:10.1158/1078-0432.CCR-12-2978.

    Article  CAS  PubMed  Google Scholar 

  13. Kidd T, Bland KS, Goodman CS. Slit is the midline repellent for the robo receptor in Drosophila. Cell. 1999;96(6):785–94.

    Article  CAS  PubMed  Google Scholar 

  14. Brose K, Bland KS, Wang KH, Arnott D, Henzel W, Goodman CS, et al. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell. 1999;96(6):795–806.

    Article  CAS  PubMed  Google Scholar 

  15. Legg JA, Herbert JM, Clissold P, Bicknell R. Slits and Roundabouts in cancer, tumour angiogenesis and endothelial cell migration. Angiogenesis. 2008;11(1):13–21. doi:10.1007/s10456-008-9100-x.

    Article  PubMed  Google Scholar 

  16. Singh RK, Indra D, Mitra S, Mondal RK, Basu PS, Roy A, et al. Deletions in chromosome 4 differentially associated with the development of cervical cancer: evidence of slit2 as a candidate tumor suppressor gene. Hum Genet. 2007;122(1):71–81. doi:10.1007/s00439-007-0375-6.

    Article  CAS  PubMed  Google Scholar 

  17. Narayan G, Goparaju C, Arias-Pulido H, Kaufmann AM, Schneider A, Durst M, et al. Promoter hypermethylation-mediated inactivation of multiple Slit-Robo pathway genes in cervical cancer progression. Mol Cancer. 2006;5:16. doi:10.1186/1476-4598-5-16.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Alvarez C, Tapia T, Cornejo V, Fernandez W, Munoz A, Camus M, et al. Silencing of tumor suppressor genes RASSF1A, SLIT2, and WIF1 by promoter hypermethylation in hereditary breast cancer. Mol Carcinog. 2013;52(6):475–87. doi:10.1002/mc.21881.

    Article  CAS  PubMed  Google Scholar 

  19. Dallol A, Krex D, Hesson L, Eng C, Maher ER, Latif F. Frequent epigenetic inactivation of the SLIT2 gene in gliomas. Oncogene. 2003;22(29):4611–6. doi:10.1038/sj.onc.1206687.

    Article  CAS  PubMed  Google Scholar 

  20. Dallol A, Morton D, Maher ER, Latif F. SLIT2 axon guidance molecule is frequently inactivated in colorectal cancer and suppresses growth of colorectal carcinoma cells. Cancer Res. 2003;63(5):1054–8.

    CAS  PubMed  Google Scholar 

  21. Qiu H, Zhu J, Yu J, Pu H, Dong R. SLIT2 is epigenetically silenced in ovarian cancers and suppresses growth when activated. Asian Pac J Cancer Prev APJCP. 2011;12(3):791–5.

    Google Scholar 

  22. Dunwell TL, Dickinson RE, Stankovic T, Dallol A, Weston V, Austen B, et al. Frequent epigenetic inactivation of the SLIT2 gene in chronic and acute lymphocytic leukemia. Epigenetics. 2009;4(4):265–9.

    CAS  PubMed  Google Scholar 

  23. Kolodkin AL, Tessier-Lavigne M. Mechanisms and molecules of neuronal wiring: a primer. Cold Spring Harbor perspectives in biology. 2011;3(6). doi:10.1101/cshperspect.a001727.

  24. Mertsch S, Schmitz N, Jeibmann A, Geng JG, Paulus W, Senner V. Slit2 involvement in glioma cell migration is mediated by Robo1 receptor. J Neurooncol. 2008;87(1):1–7. doi:10.1007/s11060-007-9484-2.

    Article  CAS  PubMed  Google Scholar 

  25. Fitamant J, Guenebeaud C, Coissieux MM, Guix C, Treilleux I, Scoazec JY, et al. Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer. Proc Natl Acad Sci USA. 2008;105(12):4850–5. doi:10.1073/pnas.0709810105.

    Article  CAS  PubMed  Google Scholar 

  26. Jones CA, Nishiya N, London NR, Zhu W, Sorensen LK, Chan AC, et al. Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nat Cell Biol. 2009;11(11):1325–31. doi:10.1038/ncb1976.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Wang B, Xiao Y, Ding BB, Zhang N, Yuan X, Gui L, et al. Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity. Cancer Cell. 2003;4(1):19–29.

    Article  PubMed  Google Scholar 

  28. Astuti D, Da Silva NF, Dallol A, Gentle D, Martinsson T, Kogner P, et al. SLIT2 promoter methylation analysis in neuroblastoma, Wilms’ tumour and renal cell carcinoma. Br J Cancer. 2004;90(2):515–21. doi:10.1038/sj.bjc.6601447.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Dallol A, Da Silva NF, Viacava P, Minna JD, Bieche I, Maher ER, et al. SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers. Cancer Res. 2002;62(20):5874–80.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work received supports from Beijing Municipal Natural Science Foundation (7122104) and the National Natural Science Foundation of China (81072395).

Conflict of interest

The authors disclose no potential conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jun Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ma, WJ., Zhou, Y., Lu, D. et al. Reduced expression of Slit2 in renal cell carcinoma. Med Oncol 31, 768 (2014). https://doi.org/10.1007/s12032-013-0768-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-013-0768-4

Keywords

Navigation