Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

Soejima, Hidenobu; Nakagawachi, Tetsuji; Zhao, Wei; Higashimoto, Ken; Urano, Takeshi; Matsukura, Shiroh; Kitajima, Yoshihiko; Takeuchi, Makoto; Nakayama, Masahiro; Oshimura, Mitsuo; Miyazaki, Kohji; Joh, Keiichiro; Mukai, Tsunehiro

doi:10.1038/sj.onc.1207576

Cited by 49 publications

(49 citation statements)

References 43 publications

(36 reference statements)

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“…Because of differences in risk factors, regional incidence is widely variable. It ranges from 5.5 to 14.9 per 100,000 individuals, but it may reach 100 per 100,000 in some regions of [40][41][42][43]. As it will be described below, one of the major mechanisms involved in the down-regulation of p27 and p57 is now believed to be the overexpression of the microRNAs (miRNAs) miR-221/222, which occurs in about 70% of HCCs [44][45][46].…”

Section: Hepatocellular Carcinoma (Hcc) Is One Of the Most Common Canmentioning

confidence: 99%

microRNA Involvement in Hepatocellular Carcinoma

Negrini

Gramantieri²,

Sabbioni³

et al. 2011

ACAMC

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Section: Hepatocellular Carcinoma (Hcc) Is One Of the Most Common Canmentioning

confidence: 99%

microRNA Involvement in Hepatocellular Carcinoma

Negrini

Gramantieri²,

Sabbioni³

et al. 2011

ACAMC

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“…Combined bisulfite restriction analyses (COBRA) using the hot-stop method were employed as described previously. 3,4 For H19-DMR, bisulfite sequencing was performed using the same primers as used for COBRA. PCR primers and conditions are shown in Supplementary Table 1.…”

Section: Methylation Analysesmentioning

confidence: 99%

Japanese and North American/European patients with Beckwith–Wiedemann syndrome have different frequencies of some epigenetic and genetic alterations

et al. 2007

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Beckwith -Wiedemann syndrome (BWS) is an imprinting-related human disease. The frequencies of causative alterations such as loss of methylation (LOM) of KvDMR1, hypermethylation of H19-DMR, paternal uniparental disomy, CDKN1C gene mutation, and chromosome abnormality have been described for North American and European patients, but the corresponding frequencies in Japanese patients have not been measured to date. Analysis of 47 Japanese cases of BWS revealed a significantly lower frequency of H19-DMR hypermethylation and a higher frequency of chromosome abnormality than in North American and European patients. These results suggest that susceptibility to epigenetic and genetic alterations differs between the two groups.

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“…We and other groups have previously reported that about 26% of HCCs exhibit a loss of maternal allele methylation at the KvDMR1 imprinted locus at 11p15.5, where CDKN1C/p57 gene is located (Schwienbacher et al, 2000;Diaz-Meyer et al, 2003), and this mechanism has been linked to reduction of CDKN1C/ p57 expression (Soejima et al, 2004). However, in unselected series of HCCs, we have observed a downregulation of CDKN1C/p57 in about 80% of HCCs with reference to matched cirrhosis, therefore CDKN1C/p57 downregulation is likely to rely upon additional molecular mechanisms besides aberrant methylation.…”

Section: Introductionmentioning

confidence: 99%

MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma

et al. 2008

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The identification of target mRNAs is a key step for assessing the role of aberrantly expressed microRNAs in human cancer. MiR-221 is upregulated in human hepatocellular carcinoma (HCC) as well as in other malignancies. One proven target of miR-221 is CDKN1B/p27, whose downregulation affects HCC prognosis. Here, we proved that the cyclin-dependent kinase inhibitor (CDKI) CDKN1C/p57 is also a direct target of miR-221. Indeed, downregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to miR-221 transfection into HCCderived cells and a significant upregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to antimiR-221 transfection. A direct interaction of miR-221 with a target site on the 3 0 UTR of CDKN1C/p57 mRNA was also demonstrated. By controlling these two CDKIs, upregulation of miR-221 can promote growth of HCC cells by increasing the number of cells in S-phase. To assess the relevance of these studies in primary tumors, matched HCC and cirrhosis samples were assayed for miR-221, for CDKN1B/p27 and CDKN1C/p57 expression. MiR-221 was upregulated in 71% of HCCs, whereas CDKN1B/p27 and CDKN1C/p57 proteins were downregulated in 77% of cases. A significant inverse correlation between miR-221 and both CDKN1B/p27 and CDKN1C/p57 was found in HCCs. In conclusion, we suggest that miR-221 has an oncogenic function in hepatocarcinogenesis by targeting CDKN1B/p27 and CDKN1C/p57, hence promoting proliferation by controlling cell-cycle inhibitors. These findings establish a basis toward the development of therapeutic strategies aimed at blocking miR-221 in HCC.

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Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

Cited by 49 publications

References 43 publications

microRNA Involvement in Hepatocellular Carcinoma

microRNA Involvement in Hepatocellular Carcinoma

Japanese and North American/European patients with Beckwith–Wiedemann syndrome have different frequencies of some epigenetic and genetic alterations

MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma

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