Alterations in DNA methylation are early, but not initial, events in ovarian tumorigenesis

Cheng, Phillip M.; Schmütte, Christoph; Cofer, Kenneth F.; Felix, Janine F.; Yu, Mimi C.; Dubeau, Louis

doi:10.1038/bjc.1997.64

Cited by 71 publications

(37 citation statements)

References 37 publications

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“…Also, 17 out of 19 ovarian epithelial carcinomas examined displayed global DNA hypomethylation relative to microdissected ovarian epithelial cystadenomas (L Dubeau, E Fiala, and M Ehrlich, unpublished data). Our results on the ovarian tumors are similar to those from an earlier study (Cheng et al 1997) in which the ovarian carcinomas had on the average 25% less m 5 C in their DNA than did the cystadenomas, which had not been microdissected. Wilms tumors and ovarian epithelial carcinomas are well suited for this kind of analysis These findings on overall genomic hypomethylation in human malignancies are in accord with early studies of rat hepatocellular carcinomas (Lapeyre and Becker, 1979;Lu et al, 1983).…”

Section: Dna Modification In Cancer: Hypo-or Hypermethylated Relativesupporting

confidence: 88%

DNA methylation in cancer: too much, but also too little

2002

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Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but these two types of epigenetic abnormalities usually seem to affect different DNA sequences. Much more of the genome is generally subject to undermethylation rather than overmethylation. Genomic hypermethylation in cancer has been observed most often in CpG islands in gene regions. In contrast, very frequent hypomethylation is seen in both highly and moderately repeated DNA sequences in cancer, including heterochromatic DNA repeats, dispersed retrotransposons, and endogenous retroviral elements. Also, unique sequences, including transcription control sequences, are often subject to cancer-associated undermethylation. The high frequency of cancer-linked DNA hypomethylation, the nature of the affected sequences, and the absence of associations with DNA hypermethylation are consistent with an independent role for DNA undermethylation in cancer formation or tumor progression. Increased karyotypic instability and activation of tumor-promoting genes by cis or trans effects, that might include altered heterochromatin-euchromatin interactions, may be important consequences of DNA hypomethylation which favor oncogenesis. The relationship of DNA hypomethylation to tumorigenesis is important to be considered in the light of cancer therapies involving decreasing DNA methylation. Inducing DNA hypomethylation may have short-term anticancer effects, but might also help speed tumor progression from cancer cells surviving the DNA demethylation chemotherapy.

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Section: Dna Modification In Cancer: Hypo-or Hypermethylated Relativesupporting

confidence: 88%

DNA methylation in cancer: too much, but also too little

2002

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“…Treatment of 8 cell lines with the de novo methyltransferase inhibitor 5-aza-2′-deoxycytidine dramatically increased ICAM-1 expression levels for all lines, suggesting that CpG island methylation may be a common mechanism of silencing of the ICAM-1 gene in ovarian adenocarcinoma. Extensive changes in global DNA methylation have been found in ovarian cancers (Cheng et al, 1997), and there is strong evidence that DNA hypermethylation plays a role in the inactivation of expression of E-cadherin, p16, BRCA1, GPC3 and hMLH1 in ovarian adenocarcinoma (Lin et al, 1999;McCluskey et al, 1999;Strathdee et al, 1999;Fearon, 2000). There was also frequent LOH at 19p13 (28%) at a similar rate to that reported in previous studies (Amfo et al, 1995;Wang et al, 1999).…”

Section: Discussionsupporting

confidence: 69%

Reduced expression of intercellular adhesion molecule-1 in ovarian adenocarcinomas

et al. 2001

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Summary Ovarian adenocarcinomas develop as the result of multiple genetic and epigenetic changes in the precursor ovarian surface epithelial (OSE) cells which result in a malignant phenotype. We investigated changes in gene expression in ovarian adenocarcinoma using a cDNA array containing 588 known human genes. We found that intercellular adhesion molecule-1 (ICAM-1) was expressed at lower levels in the ovarian tumour cell lines OAW42, PEO1 and JAM than in the immortalised human ovarian surface epithelial cell line HOSE 17.1. Further investigation revealed ICAM-1 was expressed in the surface epithelium of normal ovaries and both mRNA and protein expression levels were reduced in the majority of ovarian adenocarcinoma cell lines and primary tumours. ICAM-1 expression was increased in 8/8 cell lines treated with the de novo methyltransferase inhibitor 5-aza-2′-deoxycytidine, indicating that methylation of CpG islands may play a role in the down-regulation of its expression in primary tumours. There was a significant association between patients whose tumours expressed ICAM-1 and survival (P = 0. 1351-1358© 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.2075, available online at http://www.idealibrary.com on http://www.bjcancer.com 1987), SKOV3 (Fogh and Trempe, 1975), COLO316 (Woods et al, 1979), CAOV3 (Wong et al, 1999), OVCAR-3 (Hamilton et al, 1983) and 27/87 (derived by T Hurst) -were all maintained in RPMI 1640 with 10% FCS. Cells were harvested for RNA isolation at about 80% confluence. The cell lines OAW 42, PEO1, PEO14, JAM, SKOV3 and COLO316 were derived from serous tumours, and 27/87 was from an endometrioid tumour. The histological types of the tumours from which the cell lines HEY, CAOV3 and OVCAR3 were derived are unknown.Primary cultures of human ovarian surface epithelial (OSE) cells were prepared according to the method of Kruk et al (1990). Epithelial cells were obtained by scraping contaminating stromal cells away from proliferating epithelial sheets and were cultured in 1:1 MCDB105: Medium 199 with Earles' salts, supplemented with 20 ng ml -1 epidermal growth factor, 400 ng ml -1 hydrocortisone and 15% fetal calf serum. Their distinctive cellular morphology was used to confirm that the cultures were epithelial cells. In one case, RNA was extracted directly from the peeled epithelial cells without culturing.Ovarian adenocarcinomas were obtained from 44 patients undergoing surgery. There were 35 serous, 6 endometrioid, one mucinous and 2 clear-cell tumours. There were 43 malignant tumours and the other was of low malignant potential (LMP). All patients were staged at laparotomy, in accordance with the recommendations of the International Federation of Gynaecology and Obstetrics (FIGO). Of the malignant tumours, one was FIGO stage 1, 4 stage 2, 33 stage 3 and 5 stage 4. There were two grade 1-2, 11 grade 2, 10 grade 2/3, 17 grade 3, one grade 3-4, and 2 that were not graded. Clinicopathological data for these tumours are summarised in Table 2. Constitutional DNA was available in all ca...

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“…The results from these studies showed that borderline tumors have a methylation profile that is in between that of benign and malignant invasive tumors. In addition, data on aberrant epigenetic alterations suggest that some invasive ovarian cancers may originate through an accumulation of methylation events at specific genes in noninvasive precursor lesions (Cheng et al, 1997;Makarla et al, 2005;Tam et al, 2007). Interestingly, these studies also support the dualistic model for ovarian carcinogenesis (Shih Ie and Kurman, 2004).…”

Section: Discussionsupporting

confidence: 54%

Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells

2011

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The mechanisms underlying the progression of noninvasive serous borderline ovarian tumors (SBOT) to low-grade invasive carcinomas are poorly understood. We recently showed that inhibition of p53 induces SBOT invasion by activating the PI3K/Akt pathway and transcriptionally repressing E-cadherin. In human cancers, aberrant DNA methylation is a common phenomenon, and it is thought to be involved in the progression from noninvasive to invasive ovarian carcinomas. In this study, we tested the hypothesis that inhibition of p53 downregulates E-cadherin by regulating the methylation of its promoter in SBOT cells. Here, we show that DNA methyltransferase-1 (DNMT1), but not DNMT3a or DNMT3b, was increased in SV40 LT-infected SBOT4 cells, SBOT4-LT and the low-grade invasive serous ovarian carcinomaderived cell line MPSC1. Treatment with 5-Aza-dC, a DNMT1 inhibitor, restored E-cadherin promoter methylation and expression, and inhibited cell invasion in both invasive SBOT4-LT and MPSC1 cells. Moreover, knockdown of endogenous p53 using siRNA in SBOT3.1 cells induced DNMT1 expression and led to an increase in E-cadherin promoter methylation. Additionally, activation of the PI3K/Akt pathway is required for p53 inhibitioninduced DNMT1 expression. The increase in DNMT1 was associated with the inhibition of p53-induced downregulation of E-cadherin and cell invasion. Our findings show an important role for p53 in the progression of SBOT to an invasive carcinoma, and suggest that downregulation of E-cadherin by DNMT1-mediated promoter methylation contributes to this process.

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Alterations in DNA methylation are early, but not initial, events in ovarian tumorigenesis

Cited by 71 publications

References 37 publications

DNA methylation in cancer: too much, but also too little

DNA methylation in cancer: too much, but also too little

Reduced expression of intercellular adhesion molecule-1 in ovarian adenocarcinomas

Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells

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