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Aberrant SOX11 promoter methylation is associated with poor prognosis in gastric cancer

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Abstract

Background

Gastric cancer (GC) is the second most common cause of cancer mortality world-wide. In recent years, aberrant SOX11 expression has been observed in various solid and hematopoietic malignancies, including GC. In addition, it has been reported that SOX11 expression may serve as an independent prognostic factor for the survival of GC patients. Here, we assessed the SOX11 gene promoter methylation status in various GC cell lines and primary GC tissues, and evaluated its clinical significance.

Methods

Five GC cell lines were used to assess SOX11 expression by qRT-PCR. The effect of SOX11 expression restoration after 5-aza-2′-deoxycytidine (5-Aza-dC) treatment on GC growth was evaluated in GC cell line MKN45. Subsequently, 89 paired GC-normal gastric tissues were evaluated for their SOX11 gene promoter methylation status using methylation-specific PCR (MSP), and 20 paired GC-normal gastric tissues were evaluated for their SOX11 expression in relation to SOX11 gene promoter methylation. GC patient survival was assessed by Kaplan-Meier analyses and a Cox proportional hazard model was employed for multivariate analyses.

Results

Down-regulation of SOX11 mRNA expression was observed in both GC cell lines and primary GC tissues. MSP revealed hyper-methylation of the SOX11 gene promoter in 55.1 % (49/89) of the primary GC tissues tested and in 7.9 % (7/89) of its corresponding non-malignant tissues. The SOX11 gene promoter methylation status was found to be related to the depth of GC tumor invasion, Borrmann classification and GC differentiation status. Upon 5-Aza-dC treatment, SOX11 expression was found to be up-regulated in MKN45 cells, in conjunction with proliferation inhibition. SOX11 gene promoter hyper-methylation was found to be significantly associated with a poor prognosis and to serve as an independent marker for survival using multivariate Cox regression analysis.

Conclusions

Our results indicate that aberrant SOX11 gene promoter methylation may underlie its down-regulation in GC. SOX11 gene promoter hyper-methylation may serve as a biomarker to predict the clinical outcome of GC.

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References

  1. A. Jemal, F. Bray, M.M. Center, J. Ferlay, E. Ward, D. Forman, Global cancer statistics. CA Cancer J. Clin. 61(2), 69–90 (2011)

    Article  PubMed  Google Scholar 

  2. T.-H. Yoo, B.-K. Ryu, M.-G. Lee, S.-G. Chi, CD81 is a candidate tumor suppressor gene in human gastric cancer. Cell Oncol. 36(2), 141–153 (2013)

    Article  CAS  Google Scholar 

  3. M. Labots, T.E. Buffart, J.C. Haan, N.C.T. van Grieken, M. Tijssen, C.J.H. van de Velde, H.I. Grabsch, B. Ylstra, B. Carvalho, R.J.A. Fijneman, H.M.W. Verheul, G.A. Meijer, High-level copy number gains of established and potential drug target genes in gastric cancer as a lead for treatment development and selection. Cell Oncol. 37(1), 41–52 (2014)

    Article  CAS  Google Scholar 

  4. A. Yousuf, M.Y. BhatArshad, A. Pandith, D. Afroze, N.P. Khan, K. Alam, P. Shah, M.A. Shah, S. Mudassar, MGMT gene silencing by promoter hypermethylation in gastric cancer in a high incidence area. Cell Oncol. 37(4), 245–252 (2014)

    Article  CAS  Google Scholar 

  5. A.I. Penzo-Méndez, Critical roles for SoxC transcription factors in development and cancer. Int. J. Biochem. Cell Biol. 42(3), 425–428 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  6. E. Sock, S.D. Rettig, J. Enderich, M.R. Bösl, E.R. Tamm, M. Wegner, Gene targeting reveals a widespread role for the high-mobility-group transcription factor Sox11 in tissue remodeling. Mol. Cell. Biol. 24(15), 6635–6644 (2004)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. M. Bergsland, M. Werme, M. Malewicz, T. Perlmann, J. Muhr, The establishment of neuronal properties is controlled by Sox4 and Sox11. Genes Dev. 20(24), 3475–3486 (2006)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. L. Lin, V.M. Lee, Y. Wang, J.S. Lin, E. Sock, M. Wegner, L. Lei, Sox11 regulates survival and axonal growth of embryonic sensory neurons. Dev. Dyn. 240(1), 52–64 (2011)

    Article  CAS  PubMed  Google Scholar 

  9. Y. Wang, L. Lin, H. Lai, L.F. Parada, L. Lei, Transcription factor Sox11 is essential for both embryonic and adult neurogenesis. Dev. Dyn. 242(6), 638–653 (2013)

    Article  CAS  PubMed  Google Scholar 

  10. X. Jing, T. Wang, S. Huang, J.C. Glorioso, K.M. Albers, The transcription factor Sox11 promotes nerve regeneration through activation of the regeneration-associated gene Sprr1a. Exp. Neurol. 233(1), 221–232 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. T. Hide, T. Takezaki, Y. Nakatani, H. Nakamura, J. Kuratsu, T. Kondo, Sox11 prevents tumorigenesis of glioma-initiating cells by inducing neuronal differentiation. Cancer Res. 69(20), 7953–7959 (2009)

    Article  CAS  PubMed  Google Scholar 

  12. S. Sernbo, E. Gustavsson, D.J. Brennan, W.M. Gallagher, E. Rexhepaj, F. Rydnert, K. Jirström, C.A. Borrebaeck, S. Ek, The tumour suppressor SOX11 is associated with improved survival among high grade epithelial ovarian cancers and is regulated by reversible promoter methylation. BMC Cancer 11, 405 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. E. Gustavsson, S. Sernbo, E. Andersson, D.J. Brennan, M. Dictor, M. Jerkeman, C.A. Borrebaeck, S. Ek, SOX11 expression correlatesto promoter methylation and regulates tumor growth in hematopoietic malignancies. Mol. Cancer 9, 187 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  14. S. Zhang, S. Li, J.-L. Gao, Promoter methylation status of the tumor suppressor gene SOX11 is associated with cell growth and invasion in nasopharyngeal carcinoma. Cancer Cell Int. 13(109) (2013)

  15. W. Chung, J. Bondaruk, J. Jelinek, Y. Lotan, S. Liang, B. Czerniak, J.P. Issa, Detection of bladder cancer using novel DNA methylation biomarkers in urine sediments. Cancer Epidemiol. Biomarkers Prev. 20(7), 1483–1491 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. D.J. Brennan, S. Ek, E. Doyle, T. Drew, M. Foley, G. Flannelly, D.P. O’Connor, W.M. Gallagher, S. Kilpinen, O.P. Kallioniemi, K. Jirstrom, C. O’Herlihy, C.A. Borrebaeck, The transcription factor Sox11 is a prognostic factor for improved recurrence-free survival in epithelial ovarian cancer. Eur. J. Cancer 45(8), 1510–1517 (2009)

    Article  CAS  PubMed  Google Scholar 

  17. A. Mozos, C. Royo, E. Hartmann, D. De Jong, C. Baró, A. Valera, K. Fu, D.D. Weisenburger, J. Delabie, S.S. Chuang, E.S. Jaffe, C. Ruiz-Marcellan, S. Dave, L. Rimsza, R. Braziel, R.D. Gascoyne, F. Solé, A. López-Guillermo, D. Colomer, L.M. Staudt, A. Rosenwald, G. Ott, P. Jares, E. Campo, SOX11 expressionis highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica 94(11), 1555–1562 (2009)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. S.C. Hsiao, I.R. Cortada, L. Colomo, H. Ye, H. Liu, S.Y. Kuo, S.H. Lin, S.T. Chang, T.U. Kuo, E. Campo, S.S. Chuang, SOX11 is useful in differentiating cyclin D1-positive diffuse large B-cell lymphoma from mantle cell lymphoma. Histopathology 61(4), 685–693 (2012)

    PubMed  Google Scholar 

  19. Q. Ying, Chenfei Zhou, Jianian Zhang, Qu Cai, Jianfang Li, Tao Du, Zhenggang Zhu, Xiaojiang Cui and Bingya Liu, The metastasis suppressor SOX11 is an independent prognostic factor for improved survival in gastric cancer. Int. J. Oncol. 44(5), 1512–1520 (2014)

    Google Scholar 

  20. K.J. Livak, T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25(4), 402–408 (2001)

    Article  CAS  PubMed  Google Scholar 

  21. L.C. Li, R. Dahiya, MethPrimer: designing primers for methylation PCRs. Bioinformatics 18(11), 1427–1431 (2002)

    Article  CAS  PubMed  Google Scholar 

  22. W. Reik, J. Walter, Genomic imprinting: parental influence on the genome. Nat. Rev. Genet. 2(1), 21–32 (2001)

    Article  CAS  PubMed  Google Scholar 

  23. M. Kaneda, M. Okano, K. Hata, T. Sado, N. Tsujimoto, E. Li, H. Sasaki, Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429(6994), 900–903 (2004)

    Article  CAS  PubMed  Google Scholar 

  24. S. Yamashita, Y. Tsujino, K. Moriguchi, M. Tatematsu, T. Ushijima, Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2′-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 97(1), 64–71 (2006)

    Article  CAS  PubMed  Google Scholar 

  25. I.S. Choi, T.T. Wu, Epigenetic alterations in gastric carcinogenesis. Cell Res. 15(4), 247–254 (2005)

    Article  CAS  PubMed  Google Scholar 

  26. A. Haslinger, T.J. Schwarz, M. Covic, D.C. Lie, Expression of Sox11 in adult neurogenic niches suggests a stage-specific role in adult neurogenesis. Eur. J. Neurosci. 29(11), 2103–2114 (2009)

    Article  PubMed  Google Scholar 

  27. K.H. Ling, C.A. Hewitt, T. Beissbarth, L. Hyde, K. Banerjee, P.S. Cheah, P.Z. Cannon, C.N. Hahn, P.Q. Thomas, G.K. Smyth, S.S. Tan, T. Thomas, H.S. Scott, Molecular networks involved in mouse cerebral corticogenesis and spatio-temporal regulation of Sox4 and Sox11 novel antisense transcripts revealed by transcriptome profiling. Genome Biol. 10(10), R104 (2009)

    Article  PubMed Central  PubMed  Google Scholar 

  28. M.P. Jankowski, P.K. Cornuet, S. McIlwrath, H.R. Koerber, K.M. Albers, SRY-box containing gene 11 (Sox11) transcription factor is required for neuron survival and neurite growth. Neuroscience 143(2), 501–514 (2006)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. A. Usui, Y. Mochizuki, A. Iida, E. Miyauchi, S. Satoh, E. Sock, H. Nakauchi, H. Aburatani, A. Murakami, M. Wegner, S. Watanabe, The early retinal progenitor-expressed gene Sox11 regulates the timing of the differentiation of retinal cells. Development 140(4), 740–750 (2013)

    Article  CAS  PubMed  Google Scholar 

  30. K.M. Salerno, X. Jing, C.M. Diges, B.M. Davis, K.M. Albers, TRAF family member-associated NF-kappa B activator (TANK) expression increases in injured sensory neurons and is transcriptionally regulated by Sox11. Neuroscience 231, 28–37 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. J.M. de Bont, J.M. Kros, M.M. Passier, R.E. Reddingius, P.A. Sillevis Smitt, T.M. Luider, M.L. den Boer, R. Pieters, Differential expression and prognostic significance of SOX genes in pediatric medulloblastoma and ependymoma identified by microarray analysis. Neuro. Oncol. 10(5), 648–660 (2008)

    Article  PubMed Central  PubMed  Google Scholar 

  32. B. Weigle, R. Ebner, A. Temme, S. Schwind, M. Schmitz, A. Kiessling, M.A. Rieger, G. Schackert, H.K. Schackert, E.P. Rieber, Highly specific overexpression of the transcription factor SOX11 in human malignant gliomas. Oncol. Rep. 13(1), 139–144 (2005)

    CAS  PubMed  Google Scholar 

  33. J.E. Stuart, E.A. Lusis, A.C. Scheck, S.W. Coons, A. Lal, A. Perry, D.H. Gutmann, Identification of gene markers associated with aggressive meningioma by filtering across multiple sets of gene expression arrays. J. Neuropathol. Exp. Neurol. 70(1), 1–12 (2011)

    Article  CAS  PubMed  Google Scholar 

  34. F.J. Lopez, M. Cuadros, C. Cano, A. Concha, A. Blanco, Biomedical application of fuzzy association rules for identifying breast cancer biomarkers. Med. Biol. Eng. Comput. 50(9), 981–990 (2012)

    Article  CAS  PubMed  Google Scholar 

  35. S.D. Castillo, A. Matheu, N. Mariani, J. Carretero, F. Lopez-Rios, R. Lovell-Badge, M. Sanchez-Cespedes, Novel transcriptional targets of the SRY-HMG box transcription factor SOX4 link its expression to the development of small cell lung cancer. Cancer Res. 72(1), 176–186 (2012)

    Article  CAS  PubMed  Google Scholar 

  36. S. Murugan, J. Shan, S.J. Kühl, A. Tata, I. Pietilä, M. Kühl, S.J. Vainio, WT1 and Sox11 regulate synergistically the promoter of the Wnt4 gene that encodes a critical signal for nephrogenesis. Exp. Cell Res. 318(10), 1134–1145 (2012)

    Article  CAS  PubMed  Google Scholar 

  37. P. Conrotto, U. Andréasson, V. Kuci, C.A. Borrebaeck, S. Ek, Knock-down of SOX11 induces autotaxin-dependent increase in proliferation in vitro and more aggressive tumors in vivo. Mol Oncol 5(6), 527–537 (2011)

    Article  CAS  PubMed  Google Scholar 

  38. A.M. Wasik, M. Lord, X. Wang, F. Zong, P. Andersson, E. Kimby, B. Christensson, M. Karimi, B. Sander, SOXC transcription factors in mantle cell lymphoma: the role of promoter methylation in SOX11 expression. Sci. Rep. 3, 1400 (2013)

    Article  PubMed Central  PubMed  Google Scholar 

  39. M.C. Vegliante, C. Royo, J. Palomero, I. Salaverria, B. Balint, I. Martín-Guerrero, X. Agirre, A. Lujambio, J. Richter, S. Xargay-Torrent, S. Bea, L. Hernandez, A. Enjuanes, M.J. Calasanz, A. Rosenwald, G. Ott, J. Roman-Gomez, F. Prosper, M. Esteller, P. Jares, R. Siebert, E. Campo, J.I. Martín-Subero, V. Amador, Epigenetic activation of SOX11 in lymphoid neoplasms by histone modifications. PLoS One 6(6), e21382 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. T. Otsubo, Y. Akiyama, K. Yanagihara, Y. Yuasa, SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis. Br. J. Cancer 98(4), 824–831 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. M. Sun, H. Uozaki, R. Hino, A. Kunita, A. Shinozaki, T. Ushiku, T. Hibiya, K. Takeshita, M. Isogai, K. Takada, M. Fukayama, SOX9 expression and its methylation status in gastric cancer. Virchows Arch. 460(3), 271–279 (2012)

    Article  CAS  PubMed  Google Scholar 

  42. I. Balgkouranidou, A. Karayiannakis, D. Matthaios, H. Bolanaki, G. Tripsianis, A.A. Tentes, E. Lianidou, E. Chatzaki, A. Fiska, M. Lambropoulou, G. Kolios, S. Kakolyris, Assessment of SOX17 DNA methylation in cell free DNA from patients with operable gastric cancer. Association with prognostic variables and survival. Clin. Chem. Lab. Med. 51(7), 1505–1510 (2013)

    Article  CAS  PubMed  Google Scholar 

  43. E.C. Delot, M.E. Bahamonde, M. Zhao, K.M. Lyons, BMP signaling is required for septation of the outflow tract of the mammalian heart. Development 130(1), 209–220 (2003)

    Article  CAS  PubMed  Google Scholar 

  44. R. Yan, X. Peng, X. Yuan, D. Huang, J. Chen, Q. Lu, N. Lv, S. Luo, Suppression of growth and migration by blocking the hedgehog signaling pathway in gastric cancer cells. Cell Oncol. 36(5), 421–435 (2013)

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by a grant from the Higher Specialized Research Fund for Doctoral Program of the Ministry of Education of China (grant no. 20102104110001) and the Foundation of Liaoning Province Science and Technology Plan Project (grant no. 2013225021). The authors would like to thank the Institute of General Surgery of China Medical University for support.

Conflict of interest

The authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang, China

    Xiaoyang Xu, Zhenhua Li, Peng Deng, Xinjiang Zhu, Jian Liu, Chundong Zhang, Shuchen Chen, Dongqiu Dai & Dongqiu Dai

  2. Department of Surgery, the general hospital of Fushun mining bureau (the Seventh Affiliated Hospital of China Medical University), Fushun, China

    Xiaoyang Xu & Jiang Wang

  3. Department of Radiotherapy, The Second Hospital, Hebei Medical University, Shijiazhuang, China

    Xiaojing Chang

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  1. Xiaoyang Xu
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Xu, X., Chang, X., Li, Z. et al. Aberrant SOX11 promoter methylation is associated with poor prognosis in gastric cancer. Cell Oncol. 38, 183–194 (2015). https://doi.org/10.1007/s13402-015-0219-7

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