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Cellular Oncology
Published in: Cellular Oncology 3/2015

01-06-2015 | Original Paper

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

Authors: Xiaoyang Xu, Xiaojing Chang, Zhenhua Li, Jiang Wang, Peng Deng, Xinjiang Zhu, Jian Liu, Chundong Zhang, Shuchen Chen, Dongqiu Dai

Published in: Cellular Oncology | Issue 3/2015

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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.
Literature
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)CrossRefPubMed
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)CrossRef
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)CrossRef
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)CrossRef
5.
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMed
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)CrossRefPubMedCentralPubMed
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
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)
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)CrossRefPubMed
21.
L.C. Li, R. Dahiya, MethPrimer: designing primers for methylation PCRs. Bioinformatics 18(11), 1427–1431 (2002)CrossRefPubMed
22.
W. Reik, J. Walter, Genomic imprinting: parental influence on the genome. Nat. Rev. Genet. 2(1), 21–32 (2001)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
25.
I.S. Choi, T.T. Wu, Epigenetic alterations in gastric carcinogenesis. Cell Res. 15(4), 247–254 (2005)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMedCentralPubMed
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)PubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMedCentralPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRefPubMed
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)CrossRef
Metadata
Title
Aberrant SOX11 promoter methylation is associated with poor prognosis in gastric cancer
Authors
Xiaoyang Xu
Xiaojing Chang
Zhenhua Li
Jiang Wang
Peng Deng
Xinjiang Zhu
Jian Liu
Chundong Zhang
Shuchen Chen
Dongqiu Dai
Publication date
01-06-2015
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 3/2015
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-015-0219-7

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