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International Journal of Colorectal Disease

Published in:

01-06-2007 | Original Article

Expression of human DNA methyltransferase 1 in colorectal cancer tissues and their corresponding distant normal tissues

Authors: Yi-Min Zhu, Qiong Huang, Jie Lin, Yu Hu, Jian Chen, Mao-De Lai

Published in: International Journal of Colorectal Disease | Issue 6/2007

Abstract

Background and aim

DNA methylation plays an important role during colorectal cancer (CRC) carcinogenesis. DNA methyltransferase 1 (DNMT1) is responsible for maintaining DNA methylation. We addressed the significance of DNMT1 expression in CRC.

Materials and methods

We measured the expression of DNMT1 in CRC tissues and in their corresponding distal normal colorectal mucosa using reverse transcriptase-polymerase chain reaction and immunohistochemical analysis.

Results

The mean ± SD of DNMT1 mRNA in CRC tissues was 1.04 ± 0.36, which was significantly higher than that in their corresponding distal normal colorectal mucosa (0.58 ± 0.44, P < 0.05). Fifty-eight out of 77 (75.3%) CRC tissues and only 30 out of 77 (39%) corresponding distant normal colorectal mucosa showed immunoreactivity (P < 0.001). We also found that the immunoreactivity of DNMT1 was higher in mucosa adjacent to cancer than in corresponding normal colorectal mucosa; high immunoreactivity was significantly correlated with poor differentiation in CRC tissues (P = 0.008). No significant associations were found between DNMT1 immunoreactivity and the following variables: age, sex, locations of cancer, Duke’s phase, and the presence of lymph-node metastasis.

Conclusion

These findings suggested that DNMT1 was associated with the malignant phenotype, and dysregulation of DNMT1 expression was present in tumor cells of CRC.

Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428PubMedCrossRef

Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21:163–167PubMedCrossRef

Kanai Y, Ushijima S, Tsuda H, Sakamoto M, Hirohashi S (2000) Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis. Cancer Lett 148:73–80PubMedCrossRef

Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S (2000) Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis—a comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma. Hepatology 32:970–979PubMedCrossRef

Ueki T, Toyota M, Sohn T, Yeo CJ, Issa JP, Hruban RH, Goggins M (2000) Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res 60:1835–1839PubMed

Shen JC, Rideout WM, Jones PA (1992) High frequency mutagenesis by a DNA methyltransferase. Cell 71:1073–1080PubMedCrossRef

Momparler R, Bovenzi (2000) DNA methylation and cancer. J Cell Physiol 183:145–154PubMedCrossRef

Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R (1998) DNA hypomethylation leads to elevated mutation rates. Nature 54:89–93

Zhang J, Lai MD, Chen J (1999) Methylation status of p16 gene in colorectal carcinoma and normal colorectal mucosa. World J Gastroenterol 5:451–454PubMed

10.

Zhu YM, Lin J, Huang Q, Lai MD (2003) Screening the differentially methylated DNA sequences of colorectal cancer by methylated CpG islands amplification coupled with representational difference analysis. Chin J Med Genet 20:425–429

11.

Yen RW, Vertino PM, Nelkin BD, Yu JJ, El-Deiry W, Cumaraswamy A et al (1999) Isolation and characterization of the cDNA encoding human DNA methyltransferase. Nucleic Acids Res 59:5438–5442

12.

Leonhardt H, Page AW, Weier H (1992) A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71:865–873PubMedCrossRef

13.

Pradhan S, Bacolla A, Wells RD, Roberts RJ (1999) Recombinant human DNA (cytosine-5) methyltransferase. I. Expression, purification, and comparison of de novo and maintenance methylation. J Biol Chem 274:33002–33010PubMedCrossRef

14.

Robertson KD (2001) DNA methylation, methyltransferases, and cancer. Oncogene 20:3139–3155PubMedCrossRef

15.

Issa JP, Vertino PM, Wu J, Sazawal S, Celano P, Nelkin BD et al (1993) Increased cytosine DNA-methyltransferase activity during colon cancer progression. J Natl Cancer Inst 85:1235–1240PubMedCrossRef

16.

Sun L, Hui AM, Kanai Y, Sakamoto M, Hirohashi S (1997) Increased DNA methyltransferase expression is associated with an early stage of human hepatocarcinogenesis. Jpn J Cancer Res 88:1165–1170PubMed

17.

Saito Y, Kanai Y, Sakamoto M, Saito H, Ishii H, Hirohashi S (2001) Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis. Hepatology 33:561–568PubMedCrossRef

18.

Kanai Y, Ushijima S, Kondo Y, Nakanishi Y, Hirohashi S (2001) DNA methyltransferase expression and DNA methylation of CpG islands and pericentromeric satellite regions in human colorectal and stomach cancers. Int J Cancer 91:205–212PubMedCrossRef

19.

Eads CA, Danenberg KD, Kawakami K, Saltz LB, Danenberg PV, Laird PW (1999) CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res 59:2302–2306PubMed

20.

Paz MF, Wei S, Cigudosa JC, Rodriguez-Perales S, Peinado MA, Huang TH, Esteller M (2003) Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases. Hum Mol Genet 12:2209–2219PubMedCrossRef

21.

De Marzo AM, Marchi VL, Yang ES, Veeraswamy R, Lin X, Nelson WG (1999) Abnormal regulation of DNA methyltransferase expression during colorectal. Carcinogenesis. Cancer Res 59:3855–3860PubMed

22.

Choi MS, Shim YH, Hwa JY, Lee SK, Ro JY, Kim JS et al (2003) Expression of DNA methyltransferases in multistep hepatocarcinogenesis. Hum Pathol 34:11–17PubMedCrossRef

23.

Peng DF, Kanai Y, Sawada M, Ushijima S, Hiraoka N, Kosuge T et al (2005) Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas. Cancer Sci 96:403–408PubMedCrossRef

24.

Nakagawa T, Kanai Y, Saito Y, Kitamura T, Kakizoe T, Hirohashi S (2003) Increased DNA methyltransferase 1 protein expression in human transitional cell carcinoma of the bladder. J Urol 170:2463–2466PubMedCrossRef

25.

Etoh T, Kanai Y, Ushijima S, Nakagawa T, Nakanishi Y, Sasako M et al (2004) Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. Am J Pathol 164:689–699PubMed

26.

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):527–532PubMedCrossRef

27.

Esteller M (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21:5427–5440PubMedCrossRef

28.

Wu J, Herman JG, Wilson G, Lee RY, Yen RW, Mabry M et al (1996) Expression of prokaryotic Hha I DNA methyltransferase is transforming and lethal to NIH 3T3 cells. Cancer Res 56:616–622PubMed

29.

Bestor TH (2000) The DNA methyltransferase of mammals. Hum Mol Genet 9:2395–2402PubMedCrossRef

30.

Ting AH, Jair K, Suzuki H, Yen RC, Baylin SB, Schuebel KE (2004) Mammalian DNA methyltransferase 1: inspiration for new directions. Cell Cycle 3:1024–1026PubMed

31.

Rhee I, Jair KW, Lengauer C, Herman JG, Kinzler KW, Vogelstein B (2000) CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 404:1003–1007PubMedCrossRef

Title: Expression of human DNA methyltransferase 1 in colorectal cancer tissues and their corresponding distant normal tissues
Authors: Yi-Min Zhu
Qiong Huang
Jie Lin
Yu Hu
Jian Chen
Mao-De Lai
Publication date: 01-06-2007
Publisher: Springer-Verlag
Published in: International Journal of Colorectal Disease / Issue 6/2007
Print ISSN: 0179-1958
Electronic ISSN: 1432-1262
DOI: https://doi.org/10.1007/s00384-006-0224-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Expression of human DNA methyltransferase 1 in colorectal cancer tissues and their corresponding distant normal tissues

Abstract

Background and aim

Materials and methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background and aim

Materials and methods

Results

Conclusion

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