Methylation Status of Genes Upregulated by Demethylating Agent 5-aza-2′-Deoxycytidine in Hepatocellular Carcinoma

Hirasawa, Yuichi; Arai, Makoto; Imazeki, Fumio; Tada, Motohisa; Mikata, Rintaro; Fukai, Kenichi; Miyazaki, Masaru; Ochiai, Takenori; Saisho, Hiromitsu; Yokosuka, Osamu

doi:10.1159/000100475

Cited by 67 publications

(59 citation statements)

References 44 publications

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“…Another study has showed that the promoter regions of transgelin were highly methylated in the hepatocellular carcinoma cell lines. 40 Our observation further confirmed that treatment with 5-AzaC restored expression of transgelin mRNA and protein in HT29 cell line, but not in Lovo cell, suggesting hypermethylation of transgelin is important in the regulation of transgelin transcription in colorectal cancer. In the mean time, however, the expression of transgelin mRNA and protein in Lovo cells was not restored after treatment with 5-AzaC, indicating that transgelin expression might also be suppressed by unknown post-transcriptional regulation.…”

Section: Discussionsupporting

confidence: 81%

Transgelin as a suppressor is associated with poor prognosis in colorectal carcinoma patients

et al. 2009

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We performed comparative proteomic analysis of colorectal cancer to investigate potential target proteins correlated with carcinogenesis and prognosis. Among them, transgelin, a 22 kDa protein also called SM22, was identified as a novel tumor suppressor protein, but little is known about this protein in tumors so far. A remarkable reduced expression of transgelin was found in colorectal cancer samples compared with normal colorectal mucosa. The effect of 5-aza-2 0 -deoxycytidine as a demethylation agent would obviously restore the original expression level of transgelin, implicating DNA hypermethylation of transgelin is important in the regulation of transgelin transcription in colorectal cancer. As a control, the investigation at cell line level confirms that transgelin protein comes from epithelium but not mesenchymal cells. Further, immunohistochemical staining for transgelin was performed on paraffin sections of 62 and 126 cases of normal colorectal mucosa and colorectal cancer specimens, respectively. As compared to normal colorectal tissue, we observed a significantly lower transgelin expression in colorectal cancer samples (Po0.001). Survival analysis demonstrated that patients without transgelin expression had shorter overall survival, whereas patients with transgelin expression had better survival (P ¼ 0.006). Multivariate analysis showed that negative transgelin expression was an independent prognostic indicator for patient's survival. Our results suggest that transgelin as a suppressor may serve as important biomarker of malignancy. Loss of transgelin involves gene promoter hypermethylation and is closely associated with poor overall survival in colorectal cancer patients.

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Section: Discussionsupporting

confidence: 81%

Transgelin as a suppressor is associated with poor prognosis in colorectal carcinoma patients

et al. 2009

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“…6,30 KLF6 promoter hypermethylation has been suggested as another possible inactivating mechanism, 23,[33][34][35] although according to some authors 35 epigenetic alterations are not relevant in prostate cancer. Other studies have reported downregulation of KLF6 mRNA levels in hepatocellular carcinoma (HCC) and in lung cancer cell lines, as well as in prostate cancer cell lines.…”

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confidence: 99%

KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

et al. 2008

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Krü ppel-like factor 6 (KLF6) has been reported to act as a tumor suppressor gene involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. Many studies suggest that KLF6 is inactivated by allelic loss and somatic mutation. However, there is a high variability in the reported frequency of mutations (from 1 to 55%). TP53 also regulates the cell cycle through the activation of p21. In prostate cancer, the reported frequency of TP53 mutations ranges from 3 to 42%. In all these reports, there is a considerable degree of methodological heterogeneity. Our aim was to determine the frequency of KLF6 and TP53 mutations in a welldefined group of prostate tumors with different stages and Gleason grades. The four exons of KLF6 and exons 4-9 of TP53 were studied in 103 cases, including 90 formalin-fixed, paraffin-embedded (FFPE) and 13 frozen samples. All tumors were analyzed through PCR and direct sequencing. All changes found were confirmed by a second independent PCR and sequencing reaction. For KLF6, mutation (E227G) was only detected in one tumor (1%) and for TP53, three different mutations (L130H, H214R, and Y234C) were detected in five tumors (5%). This low mutation index is in keeping with recent papers on the subject. Our study strongly supports the notion that KLF6 and TP53 mutations are not frequent events in prostate cancer. When using FFPE tissues, it is mandatory to perform at least two independent rounds of PCR and sequencing to confirm mutations and exclude Taq polymerase-induced artifacts. Two of these genes are Krü ppel-like factor 6 (KLF6) and TP53.KLF6 is a transcription factor that interacts with DNA through three zinc-fingers in its COOHterminal domain. KLF6 belongs to the KLF family, a family that is broadly involved in cell differentiation, development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. 5 It has been suggested that KLF6 could be involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. 6 This has been proven in several in vitro 5 and in vivo assays. 7 KLF6 is believed to regulate cancer development and progression through the downregulation of the c-Jun oncoprotein 8 and the activation of E-cadherin. 9 The reported frequency of KLF6 mutations in different types of human cancer varies in the different published studies. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] In prostate cancer, four studies have analyzed the frequency of KLF6 mutations. 6,[30][31][32] In the first published study, Narla et al 6 showed a very high frequency, 55%, whereas in the following study, Chen et al 30 obtained a lower frequency, around 15%. The results of two recent reports provided frequencies of 0 and 1%. 31,32 It should be noted that there were considerable

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“…6). CSRP1 (also known as CRP1) is involved in transcription regulation during development, and reduced expression of CSRP1 has been reported in human cancers (16,17). On the other hand, OSTF1 (also known as SH3P2) interacts with the Casitas B lineage lymphoma (Cbl) proto-oncogene and is involved in the tyrosine kinase Src signaling pathway (18,19).…”

Section: Discussionmentioning

confidence: 99%

“…However, our data cannot rule out the possibility that other factors might also contribute to robust Ago binding at this CDS site. For example, circular RNAs can form base-pairing interactions with miRNAs and modulate miRNA activity by functioning as a sponge to compete for target binding (17,18). It is therefore possible that circular RNAs (circRNAs) generated from the EP300 locus may base pair with miR-HSUR4-3p and contribute to miR-HSUR4-3p-Ago clusters (Fig.…”

Section: Discussionmentioning

confidence: 99%

Herpesvirus saimiri MicroRNAs Preferentially Target Host Cell Cycle Regulators

Guo

Oei

Steitz

2015

J Virol

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In latently infected marmoset T cells, H erpesvirus saimiri (HVS) is a T-lymphotropic gammaherpesvirus that causes acute T-cell lymphomas and leukemias inNew World primates and transforms human primary T cells in vitro (1). The most abundant transcripts in HVS latently infected marmoset T cells are seven noncoding U-rich RNAs, known as HSURs (H. saimiri U-rich RNAs) (2). The functions of these viral noncoding RNAs are not well understood. HSUR1 forms base-pairing interactions with a host microRNA (miRNA), miR-27, targeting it for rapid degradation (3). This helps to promote constitutive activation of infected T cells and viral latency (4, 5). We recently discovered that, in addition to the HSURs, HVS expresses during latency another class of noncoding RNAs: six miRNAs called miR-HSURs (6). The miR-HSURs are cotranscribed together with the HSURs to give rise to chimeric primary transcripts, which are then processed via a combination of canonical and noncanonical pathways to yield mature HSURs and miRNAs (6).In complex with Argonaute (Ago) family proteins, mature miRNAs modulate target protein levels through base pairing with their mRNAs (7). Like cellular miRNAs, viral miRNAs play key regulatory roles in gene expression in host cells (8). Previous studies suggested that viral miRNAs benefit infection and the viral life cycle through regulation of (i) viral persistence, (ii) proliferation and/or survival of the infected host cells, and (iii) host immune evasion (2). Because the functions of the miR-HSURs were unknown, we embarked on the identification of their viral and cellular targets in latently infected marmoset T cells. MATERIALS AND METHODSCell culture and transfection. Marmoset (Callithrix jacchus) T cells infected with HVS strain ⌬2A (referred to as ⌬2A cells) were generated and grown as described previously (9). They were derived from marmoset peripheral blood lymphocytes immortalized by HVS and are predominantly activated CD8 cytotoxic T cells. A 1,379-bp deletion present in the

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Methylation Status of Genes Upregulated by Demethylating Agent 5-aza-2′-Deoxycytidine in Hepatocellular Carcinoma

Cited by 67 publications

References 44 publications

Transgelin as a suppressor is associated with poor prognosis in colorectal carcinoma patients

Transgelin as a suppressor is associated with poor prognosis in colorectal carcinoma patients

KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

Herpesvirus saimiri MicroRNAs Preferentially Target Host Cell Cycle Regulators

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