nach oben

Erschienen in:

01.04.2014 | Research Article

Reduced mRNA expression levels of MBD2 and MBD3 in gastric carcinogenesis

verfasst von: Thaís Brilhante Pontes, Elizabeth Suchi Chen, Carolina Oliveira Gigek, Danielle Queiroz Calcagno, Fernanda Wisnieski, Mariana Ferreira Leal, Samia Demachki, Paulo Pimentel Assumpção, Ricardo Artigiani, Laércio Gomes Lourenço, Rommel Rodriguez Burbano, Marília Arruda Cardoso Smith

Erschienen in: Tumor Biology | Ausgabe 4/2014

Einloggen, um Zugang zu erhalten

Abstract

Aberrant methylation has been reported in several neoplasias, including gastric cancer. The methyl-CpG-binding domain (MBD) family proteins have been implicated in the chromatin remodeling process, leading to the modulation of gene expression. To evaluate the role of MBD2 and MBD3 in gastric carcinogenesis and the possible association with clinicopathological characteristics, we assessed the mRNA levels and promoter methylation patterns in gastric tissues. In this study, MBD2 and MBD3 mRNA levels were determined by RT-qPCR in 28 neoplastic and adjacent nonneoplastic and 27 gastritis and non-gastritis samples. The promoter methylation status was determined by bisulfite sequencing, and we found reduced MBD2 and MBD3 levels in the neoplastic samples compared with the other groups. Moreover, a strong correlation between the MBD2 and MBD3 expression levels was observed in each set of paired samples. Our data also showed that the neoplastic tissues exhibited higher MBD2 promoter methylation than the other groups. Interestingly, the non-gastritis group was the only one with positive methylation in the MBD3 promoter region. Furthermore, a weak correlation between gene expression and methylation was observed. Therefore, our data suggest that DNA methylation plays a minor role in the regulation of MBD2 and MBD3 expression, and the presence of methylation at CpGs that interact with transcription factor complexes might also be involved in the modulation of these genes. Moreover, reduced mRNA expression of MBD2 and MBD3 is implicated in gastric carcinogenesis, and thus, further investigations about these genes should be conducted for a better understanding of the role of abnormal methylation involved in this neoplasia.

Jemal A et al. Recent trends in cutaneous melanoma incidence and death rates in the United States, 1992–2006. J Am Acad Dermatol. 2011;65(5 Suppl 1):S17–25. e1-3.PubMed

Panani AD. Cytogenetic and molecular aspects of gastric cancer: clinical implications. Cancer Lett. 2008;266(2):99–115.PubMedCrossRef

Calcagno DQ et al. DNA and histone methylation in gastric carcinogenesis. World J Gastroenterol. 2013;19(8):1182–92.PubMedCentralPubMedCrossRef

Gigek CO et al. Epigenetic mechanisms in gastric cancer. Epigenomics. 2012;4(3):279–94.PubMedCrossRef

Bogdanovic O, Veenstra GJ. DNA methylation and methyl-CpG binding proteins: developmental requirements and function. Chromosoma. 2009;118(5):549–65.PubMedCentralPubMedCrossRef

Saito M, Ishikawa F. The mCpG-binding domain of human MBD3 does not bind to mCpG but interacts with NuRD/Mi2 components HDAC1 and MTA2. J Biol Chem. 2002;277(38):35434–9.PubMedCrossRef

Zhang Y et al. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 1999;13(15):1924–35.PubMedCentralPubMedCrossRef

Le Guezennec X et al. MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Mol Cell Biol. 2006;26(3):843–51.PubMedCentralPubMedCrossRef

Ballestar E et al. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J. 2003;22(23):6335–45.PubMedCentralPubMedCrossRef

10.

Lai AY, Wade PA. Cancer biology and NuRD: a multifaceted chromatin remodelling complex. Nat Rev Cancer. 2011;11(8):588–96.PubMedCrossRef

11.

Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Immunol Scand. 1965;64:31–49.

12.

Wisnieski F et al. Reference genes for quantitative RT-PCR data in gastric tissues and cell lines. World J Gastroenterol. 2013;19(41):7121–8.PubMedCentralPubMedCrossRef

13.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8. doi:10.1006/meth.2001.1262.

14.

Carr IM et al. Sequence analysis and editing for bisulphite genomic sequencing projects. Nucleic Acids Res. 2007;35(10):e79.PubMedCentralPubMedCrossRef

15.

Farre D et al. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res. 2003;31(13):3651–3.PubMedCentralPubMedCrossRef

16.

Messeguer X et al. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002;18(2):333–4.PubMedCrossRef

17.

Lopez-Serra L et al. Unmasking of epigenetically silenced candidate tumor suppressor genes by removal of methyl-CpG-binding domain proteins. Oncogene. 2008;27(25):3556–66.PubMedCrossRef

18.

Parry L, Clarke AR. The roles of the methyl-CpG binding proteins in cancer. Cancer Gene Ther. 2011;2(6):618–30.CrossRef

19.

Sansom OJ, Maddison K, Clarke AR. Mechanisms of disease: methyl-binding domain proteins as potential therapeutic targets in cancer. Nat Clin Pract Oncol. 2007;4(5):305–15.PubMedCrossRef

20.

Amir RE et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185–8.PubMedCrossRef

21.

Calcagno DQ et al. DNA and histone methylation in gastric carcinogenesis. World J Gastroenterol. 2013;19(8):1182–92.PubMedCentralPubMedCrossRef

22.

Muller-Tidow C et al. Loss of expression of HDAC-recruiting methyl-CpG-binding domain proteins in human cancer. Br J Cancer. 2001;85(8):1168–74.PubMedCentralPubMedCrossRef

23.

Kanai Y et al. Reduced mRNA expression of the DNA demethylase, MBD2, in human colorectal and stomach cancers. Biochem Biophys Res Commun. 1999;264(3):962–6.PubMedCrossRef

24.

Maekita T et al. High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res. 2006;12(3 Pt 1):989–95.PubMedCrossRef

25.

Lima EM et al. Methylation status of ANAPC1, CDKN2A and TP53 promoter genes in individuals with gastric cancer. Braz J Med Biol Res. 2008;41(6):539–43.PubMedCrossRef

26.

Gigek CO et al. Insulin-like growth factor binding protein-3 gene methylation and protein expression in gastric adenocarcinoma. Growth Horm IGF Res. 2010;20(3):234–8.PubMedCrossRef

27.

Leal MF et al. Promoter hypermethylation of CDH1, FHIT, MTAP and PLAGL1 in gastric adenocarcinoma in individuals from northern Brazil. World J Gastroenterol. 2007;13(18):2568–74.PubMed

28.

Gigek CO et al. hTERT methylation and expression in gastric cancer. Biomarkers. 2009;14(8):630–6.PubMedCrossRef

29.

Angrisano T et al. TACC3 mediates the association of MBD2 with histone acetyltransferases and relieves transcriptional repression of methylated promoters. Nucleic Acids Res. 2006;34(1):364–72.PubMedCentralPubMedCrossRef

30.

Chatagnon A et al. Specific association between the methyl-CpG-binding domain protein 2 and the hypermethylated region of the human telomerase reverse transcriptase promoter in cancer cells. Carcinogenesis. 2009;30(1):28–34.PubMedCrossRef

31.

Hendrich B et al. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 2001;15(6):710–23.PubMedCentralPubMedCrossRef

32.

Kaji K et al. The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat Cell Biol. 2006;8(3):285–92.PubMedCrossRef

33.

Aguilera C et al. c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex. Nature. 2011;469(7329):231–5.PubMedCrossRef

34.

Sato M et al. The expression of DNA methyltransferases and methyl-CpG-binding proteins is not associated with the methylation status of p14(ARF), p16(INK4a) and RASSF1A in human lung cancer cell lines. Oncogene. 2002;21(31):4822–9.PubMedCrossRef

35.

Liu C et al. Proteomic analysis of differential proteins in pancreatic carcinomas: effects of MBD1 knock-down by stable RNA interference. BMC Cancer. 2008;8:121.PubMedCentralPubMedCrossRef

36.

Luo G et al. RNA interference of MBD1 in BxPC-3 human pancreatic cancer cells delivered by PLGA-poloxamer nanoparticles. Cancer Biol Ther. 2009;8(7):594–8.PubMedCrossRef

37.

Hendrich B, Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol. 1998;18(11):6538–47.PubMedCentralPubMed

38.

Gunther K et al. Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences. Nucleic Acids Res. 2013;41(5):3010–21.PubMedCentralPubMedCrossRef

39.

Brackertz M et al. Two highly related p66 proteins comprise a new family of potent transcriptional repressors interacting with MBD2 and MBD3. J Biol Chem. 2002;277(43):40958–66.PubMedCrossRef

40.

Tatematsu KI, Yamazaki T, Ishikawa F. MBD2-MBD3 complex binds to hemi-methylated DNA and forms a complex containing DNMT1 at the replication foci in late S phase. Genes Cells. 2000;5(8):677–88.PubMedCrossRef

41.

Watabe Y et al. Aryl hydrocarbon receptor functions as a potent coactivator of E2F1-dependent trascription activity. Biol Pharm Bull. 2010;33(3):389–97.PubMedCrossRef

42.

Xanthoulis A, Tiniakos DG. E2F transcription factors and digestive system malignancies: how much do we know? World J Gastroenterol. 2013;19(21):3189–98.PubMedCentralPubMedCrossRef

43.

Consortium EP et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74.CrossRef

44.

Chen YJ et al. Mutual regulation between microRNA-373 and methyl-CpG-binding domain protein 2 in hilar cholangiocarcinoma. World J Gastroenterol. 2012;18(29):3849–61.PubMedCentralPubMedCrossRef

45.

Yuan K et al. Decreased levels of miR-224 and the passenger strand of miR-221 increase MBD2, suppressing maspin and promoting colorectal tumor growth and metastasis in mice. Am J Gastroenterol. 2013;145(4):853–64. e9.

46.

Zhang X et al. MicroRNA-373 is upregulated and targets TNFAIP1 in human gastric cancer, contributing to tumorigenesis. Oncol Lett. 2013;6(5):1427–34.PubMedCentralPubMed

47.

Liu K et al. Increased expression of MicroRNA-221 in gastric cancer and its clinical significance. J Int Med Res. 2012;40(2):467–74.PubMedCrossRef

Titel: Reduced mRNA expression levels of MBD2 and MBD3 in gastric carcinogenesis
verfasst von: Thaís Brilhante Pontes
Elizabeth Suchi Chen
Carolina Oliveira Gigek
Danielle Queiroz Calcagno
Fernanda Wisnieski
Mariana Ferreira Leal
Samia Demachki
Paulo Pimentel Assumpção
Ricardo Artigiani
Laércio Gomes Lourenço
Rommel Rodriguez Burbano
Marília Arruda Cardoso Smith
Publikationsdatum: 01.04.2014
Verlag: Springer Netherlands
Erschienen in: Tumor Biology / Ausgabe 4/2014
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-013-1455-y

Springer Medizin

Reduced mRNA expression levels of MBD2 and MBD3 in gastric carcinogenesis

Abstract

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2014

Association of IL-6 polymorphisms with hepatocellular carcinoma risk: evidences from a meta-analysis

NOV promoted the growth and migration of pancreatic cancer cells

Association between interleukin-4 -590C > T polymorphism and non-Hodgkin’s lymphoma risk

Serum levels of macrophage migration-inhibitory factor (MIF) have diagnostic, predictive and prognostic roles in epithelial ovarian cancer patients

The microRNA networks of TGFβ signaling in cancer

Clinical significance of S100A2 expression in gastric cancer

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie