Increased DNA Methyltransferase 1 (DNMT1) Protein Expression Correlates Significantly with Poorer Tumor Differentiation and Frequent DNA Hypermethylation of Multiple CpG Islands in Gastric Cancers

Tsuyoshi Etoh, Yae Kanai, Saori Ushijima, Tohru Nakagawa, Yukihiro Nakanishi, Mitsuru Sasako, Seigo Kitano, Setsuo Hirohashi

Research output: Contribution to journalArticle

233 Citations (Scopus)

Abstract

We evaluated the significance of aberrant DNA methyltransferase 1 (DNMT1) protein expression during gastric carcinogenesis. The protein expression of DNMT1, Muc2, human gastric mucin, E-cadherin, and proliferating cell nuclear antigen was examined immunohistochemically in gastric cancers and corresponding noncancerous mucosae from 134 patients. The DNA methylation status of the CpG islands of the p16, human MutL homologue 1 (hMLH1), E-cadherin, and thrombospondin-1 (THBS-1) genes and the methylated in tumor (MINT)-1, -2, -12, and -31 clones was examined by methylation-specific polymerase chain reaction and combined bisulfite restriction enzyme analysis. Epstein-Barr virus (EBV) infection was detected by in situ hybridization. Nuclear immunoreactivity for DNMT1 was not detected in any of the noncancerous epithelia, except in proliferative zones (positive internal control), but was found in 97 (72%) of the gastric cancers. DNMT1 overexpression correlated significantly with poorer tumor differentiation (P < 0.001), but not with the phenotype (gastric type versus intestinal type) of the cancer cells. It also correlated significantly with DNA hypermethylation of the CpG islands of the hMLH1 (P = 0.024) and THBS-1 genes (P = 0.043), and with the CpG island methylator phenotype in the gastric cancers (P = 0.007). Reduced E-cadherin expression correlated significantly with poorer tumor differentiation (P = 0.002), DNA hypermethylation of the E-cadherin gene (P < 0.001) and DNMT1 overexpression (P = 0.014). DNMT1 overexpression was also associated with EBV infection (a potential etiological factor in gastric carcinogenesis) but not with the proliferative activity of the cancer cells as indicated by the proliferating cell nuclear antigen-labeling index. These results suggest that DNMT1 overexpression may not be just a secondary effect of increased cancer cell proliferative activity, but may be associated with EBV infection and other etiological factors during gastric carcinogenesis. Furthermore, DNMT1 may play a significant role in the development of poorly differentiated gastric cancers by inducing frequent DNA hypermethylation of multiple CpG islands.

Original languageEnglish
Pages (from-to)689-699
Number of pages11
JournalAmerican Journal of Pathology
Volume164
Issue number2
Publication statusPublished - 2004 Feb
Externally publishedYes

Fingerprint

Protein Methyltransferases
CpG Islands
Stomach Neoplasms
Methyltransferases
DNA
Cadherins
Neoplasms
Epstein-Barr Virus Infections
Stomach
Thrombospondin 1
Carcinogenesis
Proliferating Cell Nuclear Antigen
Gastric Mucins
Genes
Intestinal Neoplasms
Phenotype
Restriction Mapping
DNA Methylation
Methylation
In Situ Hybridization

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Increased DNA Methyltransferase 1 (DNMT1) Protein Expression Correlates Significantly with Poorer Tumor Differentiation and Frequent DNA Hypermethylation of Multiple CpG Islands in Gastric Cancers. / Etoh, Tsuyoshi; Kanai, Yae; Ushijima, Saori; Nakagawa, Tohru; Nakanishi, Yukihiro; Sasako, Mitsuru; Kitano, Seigo; Hirohashi, Setsuo.

In: American Journal of Pathology, Vol. 164, No. 2, 02.2004, p. 689-699.

Research output: Contribution to journalArticle

Etoh, Tsuyoshi ; Kanai, Yae ; Ushijima, Saori ; Nakagawa, Tohru ; Nakanishi, Yukihiro ; Sasako, Mitsuru ; Kitano, Seigo ; Hirohashi, Setsuo. / Increased DNA Methyltransferase 1 (DNMT1) Protein Expression Correlates Significantly with Poorer Tumor Differentiation and Frequent DNA Hypermethylation of Multiple CpG Islands in Gastric Cancers. In: American Journal of Pathology. 2004 ; Vol. 164, No. 2. pp. 689-699.
@article{f3a32ea262974b90a72c40fb7f2344d3,
title = "Increased DNA Methyltransferase 1 (DNMT1) Protein Expression Correlates Significantly with Poorer Tumor Differentiation and Frequent DNA Hypermethylation of Multiple CpG Islands in Gastric Cancers",
abstract = "We evaluated the significance of aberrant DNA methyltransferase 1 (DNMT1) protein expression during gastric carcinogenesis. The protein expression of DNMT1, Muc2, human gastric mucin, E-cadherin, and proliferating cell nuclear antigen was examined immunohistochemically in gastric cancers and corresponding noncancerous mucosae from 134 patients. The DNA methylation status of the CpG islands of the p16, human MutL homologue 1 (hMLH1), E-cadherin, and thrombospondin-1 (THBS-1) genes and the methylated in tumor (MINT)-1, -2, -12, and -31 clones was examined by methylation-specific polymerase chain reaction and combined bisulfite restriction enzyme analysis. Epstein-Barr virus (EBV) infection was detected by in situ hybridization. Nuclear immunoreactivity for DNMT1 was not detected in any of the noncancerous epithelia, except in proliferative zones (positive internal control), but was found in 97 (72{\%}) of the gastric cancers. DNMT1 overexpression correlated significantly with poorer tumor differentiation (P < 0.001), but not with the phenotype (gastric type versus intestinal type) of the cancer cells. It also correlated significantly with DNA hypermethylation of the CpG islands of the hMLH1 (P = 0.024) and THBS-1 genes (P = 0.043), and with the CpG island methylator phenotype in the gastric cancers (P = 0.007). Reduced E-cadherin expression correlated significantly with poorer tumor differentiation (P = 0.002), DNA hypermethylation of the E-cadherin gene (P < 0.001) and DNMT1 overexpression (P = 0.014). DNMT1 overexpression was also associated with EBV infection (a potential etiological factor in gastric carcinogenesis) but not with the proliferative activity of the cancer cells as indicated by the proliferating cell nuclear antigen-labeling index. These results suggest that DNMT1 overexpression may not be just a secondary effect of increased cancer cell proliferative activity, but may be associated with EBV infection and other etiological factors during gastric carcinogenesis. Furthermore, DNMT1 may play a significant role in the development of poorly differentiated gastric cancers by inducing frequent DNA hypermethylation of multiple CpG islands.",
author = "Tsuyoshi Etoh and Yae Kanai and Saori Ushijima and Tohru Nakagawa and Yukihiro Nakanishi and Mitsuru Sasako and Seigo Kitano and Setsuo Hirohashi",
year = "2004",
month = "2",
language = "English",
volume = "164",
pages = "689--699",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "2",

}

TY - JOUR

T1 - Increased DNA Methyltransferase 1 (DNMT1) Protein Expression Correlates Significantly with Poorer Tumor Differentiation and Frequent DNA Hypermethylation of Multiple CpG Islands in Gastric Cancers

AU - Etoh, Tsuyoshi

AU - Kanai, Yae

AU - Ushijima, Saori

AU - Nakagawa, Tohru

AU - Nakanishi, Yukihiro

AU - Sasako, Mitsuru

AU - Kitano, Seigo

AU - Hirohashi, Setsuo

PY - 2004/2

Y1 - 2004/2

N2 - We evaluated the significance of aberrant DNA methyltransferase 1 (DNMT1) protein expression during gastric carcinogenesis. The protein expression of DNMT1, Muc2, human gastric mucin, E-cadherin, and proliferating cell nuclear antigen was examined immunohistochemically in gastric cancers and corresponding noncancerous mucosae from 134 patients. The DNA methylation status of the CpG islands of the p16, human MutL homologue 1 (hMLH1), E-cadherin, and thrombospondin-1 (THBS-1) genes and the methylated in tumor (MINT)-1, -2, -12, and -31 clones was examined by methylation-specific polymerase chain reaction and combined bisulfite restriction enzyme analysis. Epstein-Barr virus (EBV) infection was detected by in situ hybridization. Nuclear immunoreactivity for DNMT1 was not detected in any of the noncancerous epithelia, except in proliferative zones (positive internal control), but was found in 97 (72%) of the gastric cancers. DNMT1 overexpression correlated significantly with poorer tumor differentiation (P < 0.001), but not with the phenotype (gastric type versus intestinal type) of the cancer cells. It also correlated significantly with DNA hypermethylation of the CpG islands of the hMLH1 (P = 0.024) and THBS-1 genes (P = 0.043), and with the CpG island methylator phenotype in the gastric cancers (P = 0.007). Reduced E-cadherin expression correlated significantly with poorer tumor differentiation (P = 0.002), DNA hypermethylation of the E-cadherin gene (P < 0.001) and DNMT1 overexpression (P = 0.014). DNMT1 overexpression was also associated with EBV infection (a potential etiological factor in gastric carcinogenesis) but not with the proliferative activity of the cancer cells as indicated by the proliferating cell nuclear antigen-labeling index. These results suggest that DNMT1 overexpression may not be just a secondary effect of increased cancer cell proliferative activity, but may be associated with EBV infection and other etiological factors during gastric carcinogenesis. Furthermore, DNMT1 may play a significant role in the development of poorly differentiated gastric cancers by inducing frequent DNA hypermethylation of multiple CpG islands.

AB - We evaluated the significance of aberrant DNA methyltransferase 1 (DNMT1) protein expression during gastric carcinogenesis. The protein expression of DNMT1, Muc2, human gastric mucin, E-cadherin, and proliferating cell nuclear antigen was examined immunohistochemically in gastric cancers and corresponding noncancerous mucosae from 134 patients. The DNA methylation status of the CpG islands of the p16, human MutL homologue 1 (hMLH1), E-cadherin, and thrombospondin-1 (THBS-1) genes and the methylated in tumor (MINT)-1, -2, -12, and -31 clones was examined by methylation-specific polymerase chain reaction and combined bisulfite restriction enzyme analysis. Epstein-Barr virus (EBV) infection was detected by in situ hybridization. Nuclear immunoreactivity for DNMT1 was not detected in any of the noncancerous epithelia, except in proliferative zones (positive internal control), but was found in 97 (72%) of the gastric cancers. DNMT1 overexpression correlated significantly with poorer tumor differentiation (P < 0.001), but not with the phenotype (gastric type versus intestinal type) of the cancer cells. It also correlated significantly with DNA hypermethylation of the CpG islands of the hMLH1 (P = 0.024) and THBS-1 genes (P = 0.043), and with the CpG island methylator phenotype in the gastric cancers (P = 0.007). Reduced E-cadherin expression correlated significantly with poorer tumor differentiation (P = 0.002), DNA hypermethylation of the E-cadherin gene (P < 0.001) and DNMT1 overexpression (P = 0.014). DNMT1 overexpression was also associated with EBV infection (a potential etiological factor in gastric carcinogenesis) but not with the proliferative activity of the cancer cells as indicated by the proliferating cell nuclear antigen-labeling index. These results suggest that DNMT1 overexpression may not be just a secondary effect of increased cancer cell proliferative activity, but may be associated with EBV infection and other etiological factors during gastric carcinogenesis. Furthermore, DNMT1 may play a significant role in the development of poorly differentiated gastric cancers by inducing frequent DNA hypermethylation of multiple CpG islands.

UR - http://www.scopus.com/inward/record.url?scp=1542319832&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1542319832&partnerID=8YFLogxK

M3 - Article

C2 - 14742272

AN - SCOPUS:1542319832

VL - 164

SP - 689

EP - 699

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 2

ER -