| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |



From the Pathology Division,* National Cancer Center Research Institute, Tokyo, Japan; the Gastric Surgery Division,
National Cancer Center Hospital, Tokyo, Japan; and the Department of Surgery I,
Oita Medical University, Oita, Japan
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.
This article has been cited by other articles:
![]() |
W. Ji, L. Yang, L. Yu, J. Yuan, D. Hu, W. Zhang, J. Yang, Y. Pang, W. Li, J. Lu, et al. Epigenetic silencing of O6-methylguanine DNA methyltransferase gene in NiS-transformed cells Carcinogenesis, June 1, 2008; 29(6): 1267 - 1275. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Yoshida, A. Kokubu, K. Suzuki, H. Kuribayashi, K. Tsuta, Y. Matsuno, M. Kusumoto, Y. Kanai, H. Asamura, S. Hirohashi, et al. Molecular Markers and Changes of Computed Tomography Appearance in Lung Adenocarcinoma with Ground-grass Opacity Jpn. J. Clin. Oncol., December 18, 2007; (2007) hym139v1. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Kanai and S. Hirohashi Alterations of DNA methylation associated with abnormalities of DNA methyltransferases in human cancers during transition from a precancerous to a malignant state Carcinogenesis, December 1, 2007; 28(12): 2434 - 2442. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Napieralski, K. Ott, M. Kremer, K. Becker, A.-L. Boulesteix, F. Lordick, J. R. Siewert, H. Hofler, and G. Keller Methylation of Tumor-Related Genes in Neoadjuvant-Treated Gastric Cancer: Relation to Therapy Response and Clinicopathologic and Molecular Features Clin. Cancer Res., September 1, 2007; 13(17): 5095 - 5102. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. E. Brown and M. Szyf Epigenetic Programming of the rRNA Promoter by MBD3 Mol. Cell. Biol., July 1, 2007; 27(13): 4938 - 4952. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. T. Agoston, P. Argani, A. M. De Marzo, J. L. Hicks, and W. G. Nelson Retinoblastoma Pathway Dysregulation Causes DNA Methyltransferase 1 Overexpression in Cancer via MAD2-Mediated Inhibition of the Anaphase-Promoting Complex Am. J. Pathol., May 1, 2007; 170(5): 1585 - 1593. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Miremadi, M. Z. Oestergaard, P. D.P. Pharoah, and C. Caldas Cancer genetics of epigenetic genes Hum. Mol. Genet., April 15, 2007; 16(R1): R28 - R49. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. Humar, R. Fukuzawa, V. Blair, A. Dunbier, H. More, A. Charlton, H. K. Yang, W. H. Kim, A. E. Reeve, I. Martin, et al. Destabilized Adhesion in the Gastric Proliferative Zone and c-Src Kinase Activation Mark the Development of Early Diffuse Gastric Cancer Cancer Res., March 15, 2007; 67(6): 2480 - 2489. [Abstract] [Full Text] [PDF] |
||||
![]() |
P.-O. Esteve, H. G. Chin, and S. Pradhan Molecular Mechanisms of Transactivation and Doxorubicin-mediated Repression of survivin Gene in Cancer Cells J. Biol. Chem., January 26, 2007; 282(4): 2615 - 2625. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. H. Ting, K. M. McGarvey, and S. B. Baylin The cancer epigenome--components and functional correlates Genes & Dev., December 1, 2006; 20(23): 3215 - 3231. [Abstract] [Full Text] [PDF] |
||||
![]() |
D.-F. Peng, Y. Kanai, M. Sawada, S. Ushijima, N. Hiraoka, S. Kitazawa, and S. Hirohashi DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas Carcinogenesis, June 1, 2006; 27(6): 1160 - 1168. [Abstract] [Full Text] [PDF] |
||||
![]() |
M.-S. Chang, H. Uozaki, J.-M. Chong, T. Ushiku, K. Sakuma, S. Ishikawa, R. Hino, R. R. Barua, Y. Iwasaki, K. Arai, et al. CpG Island M;ethylation Status in Gastric Carcinoma with and without Infection of Epstein-Barr Virus. Clin. Cancer Res., May 15, 2006; 12(10): 2995 - 3002. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. T. McCabe, J. A. Low, S. Daignault, M. J. Imperiale, K. J. Wojno, and M. L. Day Inhibition of DNA Methyltransferase Activity Prevents Tumorigenesis in a Mouse Model of Prostate Cancer Cancer Res., January 1, 2006; 66(1): 385 - 392. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. T. Agoston, P. Argani, S. Yegnasubramanian, A. M. De Marzo, M. A. Ansari-Lari, J. L. Hicks, N. E. Davidson, and W. G. Nelson Increased Protein Stability Causes DNA Methyltransferase 1 Dysregulation in Breast Cancer J. Biol. Chem., May 6, 2005; 280(18): 18302 - 18310. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. T. McCabe, J. N. Davis, and M. L. Day Regulation of DNA Methyltransferase 1 by the pRb/E2F1 Pathway Cancer Res., May 1, 2005; 65(9): 3624 - 3632. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Sung, J. Turner, S. McCarthy, S. Enkemann, C. G. Li, P. Yan, T. Huang, and T. J. Yeatman Oncogene regulation of tumor suppressor genes in tumorigenesis Carcinogenesis, February 1, 2005; 26(2): 487 - 494. [Abstract] [Full Text] [PDF] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |