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BMC Cancer
Published in: BMC Cancer 1/2002

Open Access 01-12-2002 | Research article

Methylation and silencing of the retinoic acid receptor-β2 gene in cervical cancer

Authors: Tatyana Ivanova, Anatolii Petrenko, Tatyana Gritsko, Svetlana Vinokourova, Ernest Eshilev, Vera Kobzeva, Fjodor Kisseljov, Natalia Kisseljova

Published in: BMC Cancer | Issue 1/2002

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Abstract

Background

Expression of the retinoic acid receptor β2 (RAR-β2), a putative tumor suppressor gene, is reduced in various human cancers, including squamous cell carcinomas (SCC) of the uterine cervix. The mechanism of the inhibition of RAR-β2 expression remains obscure. We examined whether methylation of RAR-β2 gene could be responsible for this silencing in cervical SCC.

Methods

Expression of RAR-β2 mRNA and methylation status of the 5' region of RAR-β2 gene were examined in 20 matched specimens from patients with cervical SCC and in three cervical cancer cell lines by Northern blot analysis and methylation-specific PCR (MSP) assay or Southern blot analysis respectively.

Results

In 8 out 20 cervical SCC (40%) the levels of RAR-β2 mRNA were decreased or undetectable in comparison with non-neoplastic cervix tissues. All 8 tumors with reduced levels of RAR-β2 mRNA expression showed methylation of the promoter and the first exon expressed in the RAR-β2 transcript. The RAR-β2 gene from non-neoplastic cervical tissues was mostly unmethylated and expressed, but methylated alleles of the gene were found in three samples of the morphologically normal tissues adjacent to the tumors. Three cervical cancer cell lines with extremely low level of RAR-β2 mRNA expression, SiHA, HeLA and CaSki, also showed methylation of this region of the RAR-β2 gene.

Conclusions

These findings suggest that methylation of the 5' region of RAR-β2 gene may contribute to gene silencing and that methylation of this region may be an important and early event in cervical carcinogenesis. These findings may be useful to make retinoids more effective as preventive and therapeutic agents in combination with inhibitors of DNA methylation.
Appendix
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Literature
1.
Gudas LJ, Sporn MB, Roberts AB: Cellular biology and biochemistry of the retinoids. In: The retinoids: biology, chemistry and medicine. Edited by: Sporn MB, Roberts AB, Goodman DS. 1994, New-York, Raven Press, 443-516.
2.
3.
Hong WK, Itri LM: Retinoids and human cancer. In: The retinoids: biology, chemistry and medicine. Edited by: Sporn MB, Roberts AB, Goodman DS. 1994, New-York, Raven Press, 387-442.
4.
Chambon P: The retinoid signaling pathway: molecular and genetic analyses. Semin Cell Biol. 1994, 5: 115-125. 10.1006/scel.1994.1015.CrossRefPubMed
5.
de The H, Marchino A, Tiollais P, Dejean A: Differential expression and ligand regulation of the retinoic acid receptor α and β genes. EMBO J. 1989, 8: 429-433.PubMedPubMedCentral
6.
de The H, Vivanco Ruiz M, Tiollais P, Stunnenberg H, Dejean A: Identification of retinoic responsive element in the retinoic acid receptor gene. Nature. 1990, 343: 177-180. 10.1038/343177a0.CrossRefPubMed
7.
Nervi C, Vollberg TM, George MD, Zelent A, Chambon P, Jetten AM: Expression of nuclear retinoic acid receptors in normal tracheobronchial cells and in lung carcinoma cells. Exp Cell Res. 1991, 195: 163-170.CrossRefPubMed
8.
Swisshelm K, Ryan K, Lee X, Tsou HC, Peacocke M, Sager R: Down-regulation of retinoic acid receptor β in mammary carcinoma cell lines and its up-regulation in senescing normal mammary epithelial cells. Cell Growth Differ. 1994, 5: 133-141.PubMed
9.
Caliaro MJ, Marmouget C, Guichard S: Response of four ovarian carcinoma cell lines to all-trans retinoic acid: relationship with induction of differentiation and retinoic acid receptor expression. Int J Cancer. 1994, 56: 743-748.CrossRefPubMed
10.
Comerci JT, Hallam S, Goldberg GL, Runowcz CD, Fields AL, Wadler S, Gallagher RE: Expression of retinoic acid receptor-β2 mRNA in normal cervical epithelium and cervical squamous cell carcinoma. Int J Oncology. 1997, 11: 983-988.
11.
Xu XC, Ro JY, Lee JS, Shin DM, Hong WK, Lotan R: Differential expression of nuclear retinoid receptors in normal, premalignant and malignant head and neck tissues. Cancer Res. 1994, 54: 3580-3587.PubMed
12.
Houle B, Rochette-Egly C, Bradley WE: Tumor-suppressive effect of the retinoic acid receptor β in human epidermoid lung cancer cells. Proc Nat Acad Sci USA. 1993, 90: 985-998.CrossRefPubMedPubMedCentral
13.
Sabichi AL, Hendrics DT, Bober MA, Birrer MJ: Retinoic acid receptor p expression and growth inhibition of gynecologic cancer cells by the synthetic retinoid N-(4-hydroxyphenyl) retinamide. J Natl Cancer Inst. 1998, 90: 597-605. 10.1093/jnci/90.8.597.CrossRefPubMed
14.
Zur Hausen H: Papillomavirus infections – a major cause of human cancers. Biochim Biophys Acta. 1996, 1288: F55-F78. 10.1016/0304-419X(96)00020-0.PubMed
15.
Bartsch D, Boye B, Baust C, zur Hausen H, Schwarz E: Retinoic acid-mediated repression of human papillomavirus 18 transcription and different ligand regulation of retinoic acid receptor β gene in nontumorogenic and tumorogenic HeLa hybrid cells. EMBO J. 1992, 11: 2283-2291.PubMedPubMedCentral
16.
Baust C, Redpath L, Schwarz E: Different ligand responsiveness of human retinoic acid receptor p gene transcription in tumorogenic and nontumorigenic cervical carcinoma-derived cell lines is mediated through a large retinoic acid response domain. Int J Cancer. 1996, 67: 409-416. 10.1002/(SICI)1097-0215(19960729)67:3<409::AID-IJC16>3.0.CO;2-2.CrossRefPubMed
17.
Hong WK, Lippman SM, Hittelman WN, Lotan R: Retinoid chemoprevention of aerodigestive cancer: from basic research to the clinic. Clinic Cancer Res. 1995, 1: 677-686.
18.
Khan MA, Jenkins GR, Tolleson WH, Creek KE, Pirisi L: Retinoic acid inhibition of human papillomavirus mediated transformation of human keratinocytes. Cancer Res. 1993, 53: 905-909.PubMed
19.
Meyskens FL, Surwit E, Moon TE, Childers JM, Davis JR, Dorr RT, Jonson CS, Alberts DS: Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans retinoic acid: a randomized trial. J Natl Cancer Inst. 1994, 86: 539-543.CrossRefPubMed
20.
Lippman SM, Kavanagh JJ, Parades-Espinoza M, Delljadillo-Madrueno F, Paredes-P Casillas, Hong WK, Massimini G, Holdener EE, Kazakoff IH: 13-cis-retinoic acid plus iterferon-α2a in locally advanced squamous cell carcinoma of cervix. J Natl Cancer Inst. 1993, 85: 499-500.CrossRefPubMed
21.
Geraddts J, Chen JY, Russell EA, Yankaskas JR, Nieves L, Minna JD: Human cancer cell lines exhibit resistance to retinoic acid treatment. Cell Growth Differ. 1993, 4: 799-809.
22.
Geisen C, Denk C, Gremm B, Baust C, Karger A, Bollag W, Schwarz E: High-level expression of the retinoic acid receptor β gene in normal cells of the uterine cervix is regulated by the retinoic acid receptor a and is abnormally down-regulated in cervical carcinoma cells. Cancer Res. 1997, 57: 1460-1467.PubMed
23.
Herman JG: Hypermethylation of tumor suppressor genes in cancer. Semin Cancer Biol. 1999, 9: 359-367. 10.1006/scbi.1999.0138.CrossRefPubMed
24.
AP Bird: CpG-rich islands and the function of DNA methylation. Nature. 1986, 321: 209-213.CrossRef
25.
Cote S, Monparler R: Activation of the retinoic acid receptor β gene by 5-aza-2'-deoxycytidine in human DLD-1 colon carcinoma cells. Anti-Cancer Drugs. 1997, 8: 56-61.CrossRefPubMed
26.
Cote S, Sinnett D, Monparler RL: Demethylation by 5-aza-2'-deoxycytidine of specific 5-methylcytosine sites in the promoter region of the retinoic acid receptor β gene in human colon carcinoma cells. Anti-Cancer Drugs. 1998, 9: 743-750.CrossRefPubMed
27.
Bovenzi V, Le NLO, Cote S, Sinnett D, Monparler L, Monparler RL: DNA methylation of retinoic acid receptor β in breast cancer and possible therapeutic role of 5-aza-2'-deoxycytidine. Anti-Cancer Drugs. 1999, 10: 471-476.CrossRefPubMed
28.
Widschwendter M, Berger J, Hermann M, Muller HM, Amberger A, Zeschnigk M, Widschwendter A, Abendstein B, Zeimet AG, Daxenbichler G, et al: Methylation and silencing of the retinoic acid receptor-β2 gene in breast cancer. J Natl Cancer Inst. 2000, 92: 826-832. 10.1093/jnci/92.10.826.CrossRefPubMed
29.
Arapshian A, Kuppumbatti YS, Mira-y-Lopez R: Methylation of conserved CpG cites neighboring the beta retinoic acid response element may mediate retinoic acid receptor beta gene silencing in MCF-7 breast cancer cells. Oncogene. 2000, 19: 4066-4070. 10.1038/sj/onc/1203734.CrossRefPubMed
30.
Samoylova E, Shaikhaiev G, Petrov S, Kisseljova N, Kisseljov F: HPV infection in cervical-cancer cases in Russia. Int J Cancer. 1995, 61: 337-341.CrossRefPubMed
31.
Sambrook J, Fritsh EF, Maniatis T: Molecular Cloning. A Laboratory Manual. Cold Spring Harbor, Cold Spring Harbor Press. 1989
32.
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB: Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA. 1996, 93: 9821-9826. 10.1073/pnas.93.18.9821.CrossRefPubMedPubMedCentral
33.
34.
Virmani AK, Muller C, Rathi A, Zoechbauer-Muleller S, Mathis M, Gazdar AF: Aberrant methylation during cervical carcinogenesis. Clin Cancer Res. 2001, 7: 584-589.PubMed
35.
Wu Q, Li Y, Liu R, Agadir A, Lee MO, Lui Y: Modulation of retinoic acid sensitivity in lung cancer cells through dynamic balance of orphan receptors nur77 and COUP-TF and their heterodimerization. EMBO J. 1997, 16: 1656-1669. 10.1093/emboj/16.7.1656.CrossRefPubMedPubMedCentral
Metadata
Title
Methylation and silencing of the retinoic acid receptor-β2 gene in cervical cancer
Authors
Tatyana Ivanova
Anatolii Petrenko
Tatyana Gritsko
Svetlana Vinokourova
Ernest Eshilev
Vera Kobzeva
Fjodor Kisseljov
Natalia Kisseljova
Publication date
01-12-2002
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2002
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-2-4

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