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Clinical Oral Investigations
Published in: Clinical Oral Investigations 1/2017

01-01-2017 | Original Article

Prognostic value of the DNMTs mRNA expression and genetic polymorphisms on the clinical outcome in oral cancer patients

Authors: Gordana Supic, Ruzica Kozomara, Katarina Zeljic, Nebojsa Jovic, Zvonko Magic

Published in: Clinical Oral Investigations | Issue 1/2017

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Abstract

Objectives

Although the importance of the epigenetic changes in tumors, including oral squamous cell carcinomas (OSCCs), is now becoming apparent, the mechanisms that trigger or cause aberrant DNA methylation in cancer are still unrevealed. DNA methylation is regulated by a family of enzymes, DNA methyltransferases (DNMTs). DNMT gene expression analysis, as well as genetic polymorphisms, has not been previously evaluated in OSCC.

Materials and methods

In 65 OSCC patients, SYBR Green real-time PCR method was assessed for relative quantification of DNMT1, DNMT3A, and DNMT3B mRNAs, normalized to TATA-binding protein (TBP) mRNA. The expression levels of all three genes were dichotomized as high or low, with a twofold change of normalized mRNA expression used as the cutoff value. Polymorphisms in DNMT1 (rs2228612) and DNMT3B (rs406193) were analyzed in 99 OSCCs by TaqMan SNPs genotyping assays.

Results

DNMT1, DNMT3A, and DNMT3B were overexpressed in 36.9, 26, and 23 % of the OSCC patients, respectively. DNMT1 overexpression was significantly associated with the overall survival, p = 0.029, and relapse-free survival of OSCC patients, p = 0.003. Patients with DNMT1 overexpression, as an independent prognostic factor, had a 2.385 times higher risk to relapse than those with lower expression. The DNMT1 A201G gene polymorphism was associated with a reduced overall survival in OSCC patients, p = 0.036.

Conclusions

Our results suggest that DNMT1 could play an important role in modulating OSCC patient survival.

Clinical relevance

DNMT gene expression could be a potential prognostic marker that might lead to an improvement in diagnosis, prognosis, and prospective use of epigenetic-targeted therapy of OSCC.
Appendix
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Literature
1.
2.
Mascolo M, Siano M, Ilardi G, Russo D, Merolla F, De Rosa G, Staibano S (2012) Epigenetic disregulation in oral cancer. Int J Mol Sci 13(2):2331–2353CrossRefPubMedPubMedCentral
3.
4.
Esteller M (2007) Epigenetic gene silencing in cancer: the DNA hypermethylome. Human Molecular Genetics. 16:R50–R59CrossRefPubMed
5.
Deng D, Liu Z, Du Y (2010) Epigenetic alterations as cancer diagnostic, prognostic, and predictive biomarkers. Adv Genet 71:125–176PubMed
6.
7.
Supic G, Kozomara R, Brankovic-Magic M, Jovic N, Magic Z (2009) Gene hypermethylation in tumor tissue of advanced oral squamous cell carcinoma patients. Oral Oncol 45:1051–1057CrossRefPubMed
8.
Supic G, Kozomara R, Jovic N, Zeljic K, Magic Z (2011) Prognostic significance of tumor-related genes hypermethylation detected in cancer-free surgical margins of oral squamous cell carcinomas. Oral Oncol 47:702–708CrossRefPubMed
9.
Kar S, Deb M, Sengupta D, Shilpi A, Parbin S, Torrisani J, Pradhan S, Patra S (2012) An insight into the various regulatory mechanisms modulating human DNA methyltransferase 1 stability and function. Epigenetics. 7(9):994–1007CrossRefPubMedPubMedCentral
10.
Jair KW, Bachman KE, Suzuki H, Ting AH, Rhee I, Yen RW, Baylin SB, Schuebel KE (2006) De novo CpG island methylation in human cancer cells. Cancer Res 66(2):682–692CrossRefPubMed
11.
RK L, YC W (2014) Dysregulated transcriptional and post-translational control of DNA methyltransferases in cancer. Cell Biosci 4:–46
12.
Girault I, Tozlu S, Lidereau R, Bieche I (2003) Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas. Clin Canc Res 9:4415–4422
13.
Mutze K, Langer R, Schumacher F, Becker K, Ott K, Novotny A, Hapfelmeier A, Höfler H, Keller G (2011) DNA methyltransferase 1 as a predictive biomarker and potential therapeutic target for chemotherapy in gastric cancer. Eur J Cancer 47(12):1817–1825CrossRefPubMed
14.
Xing J, Stewart D, Gu J, Lu C, Spitz M, Wu X (2008) Expression of methylation-related genes is associated with overall survival in patients with non-small cell lung cancer. Br J Cancer 98:1716–1722CrossRefPubMedPubMedCentral
15.
Agoston AT, Argani P, Yegnasubramanian S, De Marzo AM, Ansari-Lari MA, Hicks JL, Davidson NE, Nelson WG (2005) Increased protein stability causes DNA methyltransferase 1 dysregulation in breast cancer. J Biol Chem. 280(18):18302–18310CrossRefPubMed
16.
Ding WJ, Fang JY, Chen XY, Peng YS (2008) The expression and clinical significance of DNA methyltransferase proteins in human gastric cancer. Dig Dis Sci 53:2083–2089CrossRefPubMed
17.
Saito Y, Kanai Y, Nakagawa T, Sakamoto M, Saito H, Ishii H, Hirohashi S (2003) Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas. Int J Cancer 105(4):527–532CrossRefPubMed
18.
Gao J, Wang L, Xu J, Zheng J, Man X, Wu H, Jin J, Wang K, Xiao H, Li S, Li Z (2013) Aberrant DNA methyltransferase expression in pancreatic ductal adenocarcinoma development and progression. J Exp Clin Cancer Res 32:86CrossRefPubMedPubMedCentral
19.
Kim H, Kwon YM, Kim JS, Han J, Shim YM, Park J, Kim DH (2006) Elevated mRNA levels of DNA methyltransferase-1 as an independent prognostic factor in primary nonsmall cell lung cancer. Cancer 107(5):1042–1049CrossRefPubMed
20.
Wang J, Xu Y, Li J, Sun X, Wang LP, Ji WY (2012) The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation in laryngeal carcinoma. Oral Oncol 48(6):541–546CrossRefPubMed
21.
Chen CC, Chen WC, Wang WH, Lu CH, Lin PY, Lee KD, Chen MF (2011) Role of DNA methyltransferase 1 in pharyngeal cancer related to treatment resistance. Head Neck. 33(8):1132–1143CrossRefPubMed
22.
Bieche I, Tozlu S, Girault I, Lidereau R (2004) Identification of a three-gene expression signature of poor-prognosis breast carcinoma. Mol Cancer 3:37CrossRefPubMedPubMedCentral
23.
Zhu J, Du S, Zhang J, Wang Y, Wu Q, Ni J (2015) Polymorphism of DNA methyltransferase 3B -149C/T and cancer risk: a meta-analysis. Med Oncol 32(1):399CrossRefPubMed
24.
Wang L, Rodriguez M, Kim ES, Xu Y, Bekele N, El-Naggar AK, Hong WK, Mao L, Oh Y (2004) A novel C/T polymorphism in the core promoter of human de novo cytosine DNA methyltransferase 3B6 is associated with prognosis in head and neck cancer. Int J Oncol 25(4):993–999PubMed
25.
Liu Z, Wang L, Wang LE, Sturgis EM, Wei Q (2008) Polymorphisms of the DNMT3B gene and risk of squamous cell carcinoma of the head and neck: a case-control study. Cancer Lett 268(1):158–165CrossRefPubMedPubMedCentral
26.
Warnakulasuriya S, Johnson NW, van der Waal I (2007) Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med 36(10):575–580CrossRefPubMed
27.
Altman DG, McShane LM, Sauerbrei W, Taube SE (2012) Reporting recommendations for tumor marker prognostic studies (REMARK): explanation and elaboration. PLoS Med 9:e1001216
28.
29.
Shaw R, Hall G, Lowe D, Bowers NL, Field JK, Risk JM, et al. (2007) CpG island methylation phenotype (CIMP) in oral cancer: associated with a marked inflammatory response and less aggressive tumour biology. Oral Oncol 43:878–886CrossRefPubMed
30.
Marsit CJ, Houseman EA, Christensen BC, Eddy K, Bueno R, Sugarbaker DJ, et al. (2006) Examination of a CpG island methylator phenotype and implications of methylation profiles in solid tumors. Cancer Res 66:10621–10629CrossRefPubMed
31.
Li X, Baker-Andresen D, Zhao Q, Marshall V, Bredy TW (2014) Methyl CpG binding domain ultra-sequencing: a novel method for identifying inter-individual and cell-type-specific variation in DNA methylation. Genes Brain Behav. 13(7):721–731CrossRefPubMed
32.
Zhao SL, Zhu ST, Hao X, Li P, Zhang ST (2011) Effects of DNA methyltransferase 1 inhibition on esophageal squamous cell carcinoma. Dis Esophagus 24(8):601–610CrossRefPubMed
33.
Hajian-Tilaki K (2013) Receiver operating characteristic (ROC) curve analysis for medical diagnostic test evaluation. Caspian J Intern Med 4(2):627–635PubMedPubMedCentral
34.
Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA (1999) The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 27(11):2291–2298CrossRefPubMedPubMedCentral
35.
Shiah SG, Chang LC, Tai KY, Lee GH, Wu CW, Shieh YS (2009) The involvement of promoter methylation and DNA methyltransferase-1 in the regulation of EpCAM expression in oral squamous cell carcinoma. Oral Oncol 45(1):e1–e8CrossRefPubMed
36.
Daniel F, Rivero ER, Modolo F, Lopes TG, Salum FG (2010) Immunohistochemical expression of DNA methyltransferases 1, 3a and 3b in oral leukoplakias and squamous cell carcinomas. Arch Oral Biol 55(12):1024–1030CrossRefPubMed
37.
Napso T, Fares F (2014) Zebularine induces prolonged apoptosis effects via the caspase-3/PARP pathway in head and neck cancer cells. Int J Oncol 44(6):1971–1979PubMed
38.
Suzuki M, Shinohara F, Endo M, Sugazaki M, Echigo S, Rikiishi H (2009) Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells. Cancer Chemother Pharmacol 64(2):223–232CrossRefPubMed
39.
Egger G, Jeong S, Escobar SG, Cortez CC, Li TW, Saito Y, Yoo CB, Jones PA, Liang G (2006) Identification of DNMT1 (DNA methyltransferase 1) hypomorphs in somatic knockouts suggests an essential role for DNMT1 in cell survival. Proc Natl Acad Sci U S A 103:14080–14085CrossRefPubMedPubMedCentral
40.
Kassis ES, Zhao M, Hong JA, Chen GA, Nguyen DM, Schrump DS (2006) Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells. J Thorac Cardiovasc Surg 131(2):298–306CrossRefPubMed
41.
Oridate N, Lotan R (2005) Suppression of DNA methyltransferase 1 levels in head and neck squamous carcinoma cells using small interfering RNA results in growth inhibition and increase in Cdk inhibitor p21. Int J Oncol 26(3):757–761PubMed
42.
Wu CT, Wu CF, Lu CH, Lin CC, Chen WC, Lin PY, Chen MF (2011) Expression and function role of DNA methyltransferase 1 in human bladder cancer. Cancer 117(22):5221–5233CrossRefPubMed
43.
Foran E, Garrity-Park M, Mureau C, Newell J, Smyrk T, Limburg P, Egan L (2010) Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6. Mol Cancer Res 8(4):471–481CrossRefPubMed
44.
Sun MY, Yang XX, Xu WW, Yao GY, Pan HZ, M L (2012) Association of DNMT1 and DNMT3B polymorphisms with breast cancer risk in Han Chinese women from South China. Genet Mol Res 11(4):4330–4341CrossRefPubMed
45.
Kullmann K, Deryal M, MF O, Schmidt W, Mahlknecht U (2013) DNMT1 genetic polymorphisms affect breast cancer risk in the central European Caucasian population. Clin Epigenetics 5(1):7CrossRefPubMedPubMedCentral
46.
Fatemi M, Hermann A, Gowher H, Jeltsch A (2002) Dnmt3a and Dnmt1 functionally cooperate during de novo methylation of DNA. Eur J Biochem 269:4981–4984CrossRefPubMed
47.
Arakawa Y, Watanabe M, Inoue N, Sarumaru M, Hidaka Y, Iwatani Y (2012) Association of polymorphisms in DNMT1, DNMT3A, DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease. Clin Exp Immunol 170(2):194–201CrossRefPubMedPubMedCentral
Metadata
Title
Prognostic value of the DNMTs mRNA expression and genetic polymorphisms on the clinical outcome in oral cancer patients
Authors
Gordana Supic
Ruzica Kozomara
Katarina Zeljic
Nebojsa Jovic
Zvonko Magic
Publication date
01-01-2017
Publisher
Springer Berlin Heidelberg
Published in
Clinical Oral Investigations / Issue 1/2017
Print ISSN: 1432-6981
Electronic ISSN: 1436-3771
DOI
https://doi.org/10.1007/s00784-016-1772-9

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