Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3 σ gene in human hepatocellular carcinoma

Iwata, Norikazu; Yamamoto, Hiroyuki; Sasaki, Shigeru; Itoh, Fumio; Suzuki, Hiromu; Kikuchi, Takefumi; Kaneto, Hiroyuki; Iku, Shouhei; Ozeki, Itaru; Karino, Yoshiyasu; Sato, Takeya; Toyota, Joji; Satoh, Masaaki; Endo, Takao; Imai, Kohzoh

doi:10.1038/sj.onc.1203898

Cited by 217 publications

(173 citation statements)

References 31 publications

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“…Genes having significant relevance in breast cancer such as nm23, BRCA1, p16, and 14-3-3σ have been reported to also be under the control of epigenetic mechanisms suggesting that hypermethylation of genes is a broad spectrum phenomenon [31][32][33][34][35][36][37][38]. Methylation of 14-3-3σ is commonly seen in prostate cancer lesions, ovarian cancer, breast and lung carcinomas [34,[39][40][41][42][43][44]. The metastasis suppressor gene, nm23 is methylated in breast cancer and re-expression of the gene following treatment with 5-aza-2′-deoxycytidine resulted in a decrease in motility of the breast cancer cells [31].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer

Metge

Frost

King

et al. 2008

Clin Exp Metastasis

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Breast Cancer Metastasis Suppressor 1 (BRMS1) suppresses metastasis of human breast cancer, ovarian cancer and melanoma in athymic mice. Studies have also shown that BRMS1 is significantly downregulated in some breast tumors, especially in metastatic disease. However, the mechanisms which regulate BRMS1 expression are currently unknown. Upon examination of the BRMS1 promoter region by methylation specific PCR (MSP) analysis, we discovered a CpG island (−3477 to −2214), which was found to be hypermethylated across breast cancer cell lines. A panel of 20 patient samples analyzed showed that 45% of the primary tumors and 60% of the matched lymph node metastases, displayed hypermethylation of BRMS1 promoter. Furthermore, we found a direct correlation between the methylation status of the BRMS1 promoter in the DNA isolated from tissues, with the loss of BRMS1 expression assessed by immunohistochemistry. There are several studies investigating the mechanism by which BRMS1 suppresses metastasis; however thus far there is no

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Section: Discussionmentioning

confidence: 99%

Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer

Metge

Frost

King

et al. 2008

Clin Exp Metastasis

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“…Including our series, epigenetic transcriptional silencing of 14-3-3s has been demonstrated in malignancies from prostate, endometrium, ovary, breast, lung, liver, skin, stomach and oral squamous cell carcinoma. [15][16][17][18]20,21,[24][25][26] Another recent immunohistochemical study has shown loss of 14-3-3s expression in prostate cancer. 27 By preselecting areas of highest Gleason score in their tumor biopsies and by using a different 14-3-3s antibody, these authors find low or absent levels of 14-3-3s in an even higher percentage of tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Following studies demonstrated epigenetic silencing of 14-3-3s expression in gastric, liver, lung, cervical, oral squamous cell carcinoma, and basal cell carcinoma of the skin. [16][17][18][19][20][21] The aims of this study were: first, to study the expression of 14-3-3s by using immunohistochemistry on a multiple tumor tissue microarrays containing a large number of urological and gynecological cancers. Second, to explore the relation between 14-3-3s expression and p53 using the D07 and the PAB240 clone recognizing wild-type and mutated p53 isoforms respectively.…”

mentioning

confidence: 99%

Downregulation of 14-3-3σ in ovary, prostate and endometrial carcinomas is associated with CpG island methylation

et al. 2005

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“…17,18 In human HCC, a number of methylation-induced inactivation of genes, such as E-cadherin, p16INK4a, 14-3-3 sigma, SOCS-1 and DLC-1, have already been documented. [19][20][21][22][23][24][25][26][27] However, there is no information on the methylation-mediated silencing of Apo D in HCC. Therefore, we first analyzed the pharmacological induction of Apo D by 5-Azacitidine in human liver cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic and prognostic values of apolipoprotein D alterations in hepatocellular carcinoma

Utsunomiya

Ogawa

Yoshinaga

et al. 2005

Intl Journal of Cancer

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We previously identified apolipoprotein D (Apo D) as a novel tumor suppressor gene based on the pharmacological unmasking of epigenetic silencing. We analyzed Apo D expression using realtime reverse transcription-PCR and evaluated its expression status based on the clinicopathological parameters of 70 patients with hepatocellular carcinoma (HCC). Immunohistochemical staining was also performed. We determined the methylation status of Apo D gene promoter by methylation-specific PCR (MSP). The Apo D gene-expression in tumor tissue was significantly lower than that in nontumor tissue (p = 0.011). A low Apo D expression significantly correlated with less-differentiated HCC ( p = 0.019). Immunohistochemical studies confirmed a decreased Apo D expression in poorly differentiated tumors. The prognosis of patients with a lower Apo D gene-expression was significantly worse than that in those with a higher expression (p = 0.028). The Apo D gene-expression was an independent prognostic factor (relative risk: 2.36, p = 0.018). An MSP assay showed a low-level of methylation in well differentiated HCC and a high-level of methylation in less differentiated tumors. Apo D may be a novel tumor suppressor gene of HCC, and its expression status may be a useful biomarker for predicting the patient outcome. ' 2005 Wiley-Liss, Inc.Key words: apolipoprotein D; hepatocellular carcinoma; histological grade; prognostic factor; methylationWe recently performed a comprehensive survey of commonly inactivated tumor suppressor genes in esophageal cancer cell lines based on functional reactivation by a demethylating agent. 1 A total of 58 silenced genes were thus identified using this approach, and one of those genes was Apolipoprotein D (Apo D). In our report, we detected the promoter hypermethylation of Apo D gene using bisulfite DNA sequencing. The methylation status of Apo D correlated closely with the Apo D expression status. Moreover, the growth suppressive activity of Apo D was also demonstrated by a colony focus assay. 1 These findings thus prompted us to analyze the clinical significance of the Apo D expression status in human cancers.Apo D, belonging to the lipocalin superfamily, is a glycoprotein of about 30 kDa found in the high-density lipoprotein fraction of human plasma. 2 The functional role of Apo D remains unclear, but the observation that this protein forms complexes with lecithin-cholesterol acyltransferase suggests that Apo D may be involved in cholesterol esterification. 3 More recently, the Apo D gene-expression was reported to be induced by retinoic acid in breast cancer cell lines. The induction of the Apo D expression was accompanied by an inhibition of cell proliferation and a progression through a more differentiated phenotype. These finding suggest that the mechanisms controlling retinoic acid-induced growth arrest, cell differentiation and Apo D synthesis may be directly coordinated in human breast cancer cells. 4 Furthermore, a low expression of Apo D determined by an immunohistochemical study was significantly as...

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Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3 σ gene in human hepatocellular carcinoma

Cited by 217 publications

References 31 publications

Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer

Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer

Downregulation of 14-3-3σ in ovary, prostate and endometrial carcinomas is associated with CpG island methylation

Clinicopathologic and prognostic values of apolipoprotein D alterations in hepatocellular carcinoma

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