Promoter hypermethylation of SOX11 promotes the progression of cervical cancer in vitro and in vivo

Li,Xiaofang; Wu,Xiaoling; Li,Yun; Cui,Yumeng; Tian,Run; Singh,Namita; Ding,Muyang; Yang,Yang; Gao,Yan'e

doi:10.3892/or.2019.6993

April-2019 Volume 41 Issue 4

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April-2019 Volume 41 Issue 4

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Article

Promoter hypermethylation of SOX11 promotes the progression of cervical cancer in vitro and in vivo

Authors:
- Xiaofang Li
- Xiaoling Wu
- Yun Li
- Yumeng Cui
- Run Tian
- Namita Singh
- Muyang Ding
- Yang Yang
- Yan'e Gao
View Affiliations / Copyright

Affiliations: Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of Obstetrics and Gynecology, The Affiliated Cixi Hospital, Wenzhou Medicine University, Cixi, Zhejiang 325000, P.R. China , Department of Orthopedics, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, P.R. China
Pages: 2351-2360
|
Published online on: February 1, 2019

https://doi.org/10.3892/or.2019.6993
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Abstract

The development of cervical cancer (CC) is a multi‑gene, multi‑step carcinogenic process that involves complex genetic and epigenetic mechanisms. SRY‑related HMG‑box gene 11 (SOX11) is a member of the SOX family of transcription factors with an emerging crucial role in the development of various tumor types. To elucidate the function of SOX11 in cervical carcinogenesis, the expression level of SOX11 during the development of human CC was analyzed by immunohistochemistry and western blot analysis. Additionally, the methylation status of the SOX11 was examined using bisulfite sequencing and methylation‑specific polymerase chain reaction. The SOX11 expression and promoter methylation in human CC cell lines were also determined. The effect of SOX11 expression restoration after 5‑aza‑2'‑deoxycytidine (5‑Aza‑dC) treatment on the CC cell proliferation ability was evaluated in CC cell lines. SOX11 was highly expressed in normal cervix (NC) and precancerous low‑grade squamous intraepithelial lesions, but weakly expressed or virtually absent in precancerous high‑grade squamous intraepithelial lesions and CC, which is consistent with the result of the western blot analysis. Hypermethylation of the SOX11 promoter was detected in CC, which was significantly higher than that in NC samples at each CpG site. The expression level of SOX11 in the CC cell lines was downregulated compared with the positive control, Tera‑1human teratoma cell line. Upon 5‑Aza‑dC treatment, SOX11 expression was significantly upregulated in the CC cell lines at the mRNA and protein levels, and cell proliferation was inhibited. The results indicated that the downregulation of SOX11 in CC is due to the hypermethylation of the SOX11 promoter region. Thus, SOX11 methylation may have a role in the growth of CC cells and cervical carcinogenesis.

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1	Ginsburg O, Bray F, Coleman MP, Vanderpuye V, Eniu A, Kotha SR, Sarker M, Huong TT, Allemani C, Dvaladze A, et al: The global burden of women's cancers: A grand challenge in global health. Lancet. 389:847–860. 2017. View Article : Google Scholar : PubMed/NCBI
2	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
3	Snijders PJ, Steenbergen RD, Heideman DA and Meijer CJ: HPV-mediated cervical carcinogenesis: Concepts and clinical implications. J Pathol. 208:152–164. 2006. View Article : Google Scholar : PubMed/NCBI
4	Voltaggio L, Cimino-Mathews A, Bishop JA, Argani P, Cuda JD, Epstein JI, Hruban RH, Netto GJ, Stoler MH, Taube JM, et al: Current concepts in the diagnosis and pathobiology of intraepithelial neoplasia: A review by organ system. CA Cancer J Clin. 66:408–436. 2016. View Article : Google Scholar : PubMed/NCBI
5	Bosch FX and de Sanjosé S: Chapter 1: Human papillomavirus and cervical cancer-burden and assessment of causality. J Natl Cancer Inst Monogr. 3–13. 2003. View Article : Google Scholar : PubMed/NCBI
6	Denny L, de Sanjose S, Mutebi M, Anderson BO, Kim J, Jeronimo J, Herrero R, Yeates K, Ginsburg O and Sankaranarayanan R: Interventions to close the divide for women with breast and cervical cancer between low-income and middle-income countries and high-income countries. Lancet. 389:861–870. 2017. View Article : Google Scholar : PubMed/NCBI
7	Castellsagué X and Muñoz N: Chapter 3: Cofactors in human papillomavirus carcinogenesis-role of parity, oral contraceptives, and tobacco smoking. J Natl Cancer Inst Monogr. 20–28. 2003. View Article : Google Scholar : PubMed/NCBI
8	Louie KS, Castellsague X, de Sanjose S, Herrero R, Meijer CJ, Shah K, Munoz N and Bosch FX; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group, : Smoking and passive smoking in cervical cancer risk: Pooled analysis of couples from the IARC multicentric case-control studies. Cancer Epidemiol Biomarkers Prev. 20:1379–1390. 2011. View Article : Google Scholar : PubMed/NCBI
9	Denslow SA, Rositch AF, Firnhaber C, Ting J and Smith JS: Incidence and progression of cervical lesions in women with HIV: A systematic global review. Int J STD AIDS. 25:163–177. 2014. View Article : Google Scholar : PubMed/NCBI
10	Markowitz LE, Tsu V, Deeks SL, Cubie H, Wang SA, Vicari AS and Brotherton JM: Human papillomavirus vaccine introduction-the first five years. Vaccine. 30 (Suppl 5):F139–F148. 2012. View Article : Google Scholar : PubMed/NCBI
11	Bruni L, Diaz M, Barrionuevo-Rosas L, Herrero R, Bray F, Bosch FX, de Sanjosé S and Castellsagué X: Global estimates of human papillomavirus vaccination coverage by region and income level: A pooled analysis. Lancet Glob Health. 4:e453–e463. 2016. View Article : Google Scholar : PubMed/NCBI
12	Solomon D, Breen N and McNeel T: Cervical cancer screening rates in the United States and the potential impact of implementation of screening guidelines. CA Cancer J Clin. 57:105–111. 2007. View Article : Google Scholar : PubMed/NCBI
13	Saavedra KP, Brebi PM and Roa JC: Epigenetic alterations in preneoplastic and neoplastic lesions of the cervix. Clin Epigenetics. 4:132012. View Article : Google Scholar : PubMed/NCBI
14	Siegel EM, Riggs BM, Delmas AL, Koch A, Hakam A and Brown KD: Quantitative DNA methylation analysis of candidate genes in cervical cancer. PLoS One. 10:e01224952015. View Article : Google Scholar : PubMed/NCBI
15	Laird PW: The power and the promise of DNA methylation markers. Nat Rev Cancer. 3:253–266. 2003. View Article : Google Scholar : PubMed/NCBI
16	Gubbay J, Collignon J, Koopman P, Capel B, Economou A, Münsterberg A, Vivian N, Goodfellow P and Lovell-Badge R: A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature. 346:245–250. 1990. View Article : Google Scholar : PubMed/NCBI
17	Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R and Goodfellow PN: A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 346:240–244. 1990. View Article : Google Scholar : PubMed/NCBI
18	Sarkar A and Hochedlinger K: The sox family of transcription factors: Versatile regulators of stem and progenitor cell fate. Cell Stem Cell. 12:15–30. 2013. View Article : Google Scholar : PubMed/NCBI
19	Castinetti F, Davis SW, Brue T and Camper SA: Pituitary stem cell update and potential implications for treating hypopituitarism. Endocr Rev. 32:453–471. 2011. View Article : Google Scholar : PubMed/NCBI
20	Weigle B, Ebner R, Temme A, Schwind S, Schmitz M, Kiessling A, Rieger MA, Schackert G, Schackert HK and Rieber EP: Highly specific overexpression of the transcription factor SOX11 in human malignant gliomas. Oncol Rep. 13:139–144. 2005.PubMed/NCBI
21	Stuart JE, Lusis EA, Scheck AC, Coons SW, Lal A, Perry A and Gutmann DH: Identification of gene markers associated with aggressive meningioma by filtering across multiple sets of gene expression arrays. J Neuropathol Exp Neurol. 70:1–12. 2011. View Article : Google Scholar : PubMed/NCBI
22	Lopez FJ, Cuadros M, Cano C, Concha A and Blanco A: Biomedical application of fuzzy association rules for identifying breast cancer biomarkers. Med Biol Eng Comput. 50:981–990. 2012. View Article : Google Scholar : PubMed/NCBI
23	Sernbo S, Gustavsson E, Brennan DJ, Gallagher WM, Rexhepaj E, Rydnert F, Jirström K, Borrebaeck CA and Ek S: The tumour suppressor SOX11 is associated with improved survival among high grade epithelial ovarian cancers and is regulated by reversible promoter methylation. BMC Cancer. 11:4052011. View Article : Google Scholar : PubMed/NCBI
24	Brennan DJ, Ek S, Doyle E, Drew T, Foley M, Flannelly G, O'Connor DP, Gallagher WM, Kilpinen S, Kallioniemi OP, et al: The transcription factor Sox11 is a prognostic factor for improved recurrence-free survival in epithelial ovarian cancer. Eur J Cancer. 45:1510–1517. 2009. View Article : Google Scholar : PubMed/NCBI
25	Gustavsson E, Sernbo S, Andersson E, Brennan DJ, Dictor M, Jerkeman M, Borrebaeck CA and Ek S: SOX11 expression correlates to promoter methylation and regulates tumor growth in hematopoietic malignancies. Mol Cancer. 9:1872010. View Article : Google Scholar : PubMed/NCBI
26	Zhang S, Li S and Gao JL: Promoter methylation status of the tumor suppressor gene SOX11 is associated with cell growth and invasion in nasopharyngeal carcinoma. Cancer Cell Int. 13:1092013. View Article : Google Scholar : PubMed/NCBI
27	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
28	Xu X, Chang X, Li Z, Wang J, Deng P, Zhu X, Liu J, Zhang C, Chen S and Dai D: Aberrant SOX11 promoter methylation is associated with poor prognosis in gastric cancer. Cell Oncol. 38:183–194. 2015. View Article : Google Scholar
29	Yao Z, Sun B, Hong Q, Yan J, Mu D, Li J, Sheng H and Guo H: The role of tumor suppressor gene SOX11 in prostate cancer. Tumour Biol. 36:6133–6138. 2015. View Article : Google Scholar : PubMed/NCBI
30	Czapiewski P, Gorczynski A, Radecka K, Wiewiora C, Haybaeck J, Adam P, Fend F, Zakrzewska M, Zakrzewski K, Liberski PP, et al: Expression of SOX11, PAX5, TTF-1 and ISL-1 in medulloblastoma. Pathol Res Pract. 212:965–971. 2016. View Article : Google Scholar : PubMed/NCBI
31	Esteller M: Epigenetics in cancer. N Engl J Med. 358:1148–1159. 2008. View Article : Google Scholar : PubMed/NCBI
32	Jones PA and Baylin SB: The epigenomics of cancer. Cell. 128:683–692. 2007. View Article : Google Scholar : PubMed/NCBI
33	Jones A, Lechner M, Fourkala EO, Kristeleit R and Widschwendter M: Emerging promise of epigenetics and DNA methylation for the diagnosis and management of women's cancers. Epigenomics. 2:9–38. 2010. View Article : Google Scholar : PubMed/NCBI
34	Szalmás A and Kónya J: Epigenetic alterations in cervical carcinogenesis. Semin Cancer Biol. 19:144–152. 2009. View Article : Google Scholar : PubMed/NCBI
35	Ronnekleiv-Kelly SM, Sharma A and Ahuja N: Epigenetic therapy and chemosensitization in solid malignancy. Cancer Treat Rev. 55:200–208. 2017. View Article : Google Scholar : PubMed/NCBI
36	Fang G, Liu J, Wang Q, Huang X, Yang R, Pang Y and Yang M: MicroRNA-223-3p regulates ovarian cancer cell proliferation and invasion by targeting SOX11 expression. Int J Mol Sci. 18:E12082017. View Article : Google Scholar : PubMed/NCBI
37	Paz MF, Fraga MF, Avila S, Guo M, Pollan M, Herman JG and Esteller M: A systematic profile of DNA methylation in human cancer cell lines. Cancer Res. 63:1114–1121. 2003.PubMed/NCBI
38	Sun M, Uozaki H, Hino R, Kunita A, Shinozaki A, Ushiku T, Hibiya T, Takeshita K, Isogai M, Takada K, et al: SOX9 expression and its methylation status in gastric cancer. Virchows Arch. 460:271–279. 2012. View Article : Google Scholar : PubMed/NCBI
39	Li H, Wang J, Xiao W, Xia D, Lang B, Wang T, Guo X, Hu Z, Ye Z and Xu H: Epigenetic inactivation of KLF4 is associated with urothelial cancer progression and early recurrence. J Urol. 191:493–501. 2014. View Article : Google Scholar : PubMed/NCBI
40	Zhao W, Hisamuddin IM, Nandan MO, Babbin BA, Lamb NE and Yang VW: Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene. 23:395–402. 2004. View Article : Google Scholar : PubMed/NCBI
41	Yang WT and Zheng PS: Promoter hypermethylation of KLF4 inactivates its tumor suppressor function in cervical carcinogenesis. PLoS One. 9:e888272014. View Article : Google Scholar : PubMed/NCBI
42	Wang X, Asplund AC, Porwit A, Flygare J, Smith CI, Christensson B and Sander B: The subcellular Sox11 distribution pattern identifies subsets of mantle cell lymphoma: Correlation to overall survival. Br J Haematol. 143:248–252. 2008. View Article : Google Scholar : PubMed/NCBI
43	Fernàndez V, Salamero O, Espinet B, Solé F, Royo C, Navarro A, Camacho F, Beà S, Hartmann E, Amador V, et al: Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res. 70:1408–1418. 2010. View Article : Google Scholar : PubMed/NCBI
44	Usui A, Iwagawa T, Mochizuki Y, Iida A, Wegner M, Murakami A and Watanabe S: Expression of Sox4 and Sox11 is regulated by multiple mechanisms during retinal development. FFBS Lett. 587:358–363. 2013. View Article : Google Scholar
45	Vegliante MC, Royo C, Palomero J, Salaverria I, Balint B, Martín-Guerrero I, Agirre X, Lujambio A, Richter J, Xargay-Torrent S, et al: Epigenetic activation of SOX11 in lymphoid neoplasms by histone modifications. PLoS One. 6:e213822011. View Article : Google Scholar : PubMed/NCBI
46	Wasik AM, Lord M, Wang X, Zong F, Andersson P, Kimby E, Christensson B, Karimi M and Sander B: SOXC transcription factors in mantle cell lymphoma: The role of promoter methylation in SOX11 expression. Sci Rep. 3:14002013. View Article : Google Scholar : PubMed/NCBI
47	Chang Y, Zhang WN, Teng LI, et al: SOX11 interacts with p53 and increases its transcriptional activity. http://en.cnki.com.cn/Journal_en/A-A006-SWTX-2010-05.htmLett Biotechnol. 2010.