MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in gastric cancer

Zhu, Akao; Xia, Jiazeng; Zuo, Junbo; Jin, Shimao; Zhou, Hong; Lubin, Yao; Huang, Hongyu; Han, Ze‐Guang

doi:10.1007/s12032-011-0134-3

Cited by 87 publications

(89 citation statements)

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“…This suggests that miR-148a may not directly target RUNX3. Previous studies have already confirmed that miR-148a could modulate DNMT1 and DNMT3B protein expression (Braconi et al, 2010;Duursma et al, 2008;Pan et al, 2010;Zhu et al, 2012). Therefore, our results show that overexpression of miR148a in gastric cancer cells might upregulate RUNX3 expression through the modulation of DNMTs.…”

Section: Overexpression Of Mir-148a Downregulated Runx3 Gene Expressionsupporting

confidence: 79%

“…In those studies we found that miR-148a was significantly downregulated in gastric cancer tissues (Zhu et al, 2012). Interestingly, in the present study an obvious correlation was observed between the expression of miR-148a and RUNX3 mRNA in the 38 pairs of tissue samples (r = 0.581, P < 0.001, Fig.…”

Section: Resultssupporting

confidence: 64%

“…In addition, DNA methylation and methylation-silenced tumor suppressor gene expression (fragile histidine triad [FHIT] and WW domain-containing oxidoreductase [WWOX]) were restored to normal, and tumorigenicity was inhibited in vitro and in vivo. In our previous studies, we confirmed that miR-148a was significantly downregulated in gastric cancer (Zhu et al, 2012). Furthermore, it has been verified that DNMT1 is a target of miR-148a (Braconi et al, 2010;Pan et al, 2010).…”

Section: Introductionsupporting

confidence: 70%

“…Our previous results showed that the silence of miR-148a and overexpression of DNMT1 may constitute an epigeneticmiRNA feedback mechanism in gastric cancer, as overexpression of DNMT1 leads to hypermethylation in the promoter region of miR-148a thus causing the silence of miR-148a, and the silence of miR-148a reduces its suppression of DNMT1 resulting in higher levels of DNMT1 and hypermethylation of miR148a (Zhu et al, 2012). We believe that in gastric cancer this miRNA-epigenetic feedback may further lead to the downregulation of methylation-sensitive genes, such as P16, RUNX3, and E-cadherin, through the hypermethylation of promoters.…”

Section: Discussionmentioning

confidence: 99%

“…The miR-148a overexpression plasmid was constructed as previously described (Zhu et al, 2012). DNMT1 siRNA (sc-35204) and DNMT3B siRNA (sc-37759) were bought from Santa Cruz Biotechnology (USA).…”

Section: Plasmid Construction and Translationmentioning

confidence: 99%

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MicroRNA-148a Can Regulate Runt-Related Transcription Factor 3 Gene Expression via Modulation of DNA Methyltransferase 1 in Gastric Cancer

Zuo

Xia

et al. 2013

Molecules and Cells

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Underexpression of the gene runt-related transcription factor 3 (RUNX3), an important tumor suppressor, is known to contribute to gastric cancer progression. However, the mechanism underlying aberrant RUNX3 expression has not been fully elucidated. We investigated the role of microRNA-148a (miR-148a) and DNA methyltransferases (DNMTs) in RUNX3 promoter methylation and gene expression. RUNX3 mRNA, RUNX3 protein, and methylation levels were assayed in human gastric cancer tissues and matched normal tissues, and AGS and BGC-823 cells by real-time reverse transcription PCR, Western blot, and methylation-specific PCR, respectively. A correlation between RUNX3 mRNA levels and that of miR-148a was also investigated in gastric cancer tissues. We found that RUNX3 mRNA levels were significantly downregulated in gastric cancer tissues compared with their matched normal tissues, and were closely associated with miR-148a expression. After treatment of human gastric cancer AGS and BGC-823 cells with the DNA methylation inhibitor 5-aza-2'-deoxycytidine, a significant increase in RUNX3 mRNA, RUNX3 protein, and the non-methylated form of the RUNX3 promoter were observed relative to untreated cells. Enforced expression of miR-148a, which can modulate DNMT1 and DNMT3B, also increased the expression of RUNX3 in gastric cancer cells. Knockdown of DNMT1 was associated with increased levels of RUNX3 mRNA and RUNX3 protein, while knockdown of DNMT3B did not have any effect on these in BGC-823 cells. Our results show that miR-148a may regulate RUNX3 expression through modulation of DNMT1-dependent DNA methylation in gastric cancer and highlight a miRNA-epigenetics regulation mechanism of gene expression.

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Section: Overexpression Of Mir-148a Downregulated Runx3 Gene Expressionsupporting

confidence: 79%

Section: Resultssupporting

confidence: 64%

Section: Introductionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Plasmid Construction and Translationmentioning

confidence: 99%

See 3 more Smart Citations

MicroRNA-148a Can Regulate Runt-Related Transcription Factor 3 Gene Expression via Modulation of DNA Methyltransferase 1 in Gastric Cancer

Zuo

Xia

et al. 2013

Molecules and Cells

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RUNX3 inhibits laryngeal squamous cell carcinoma malignancy under the regulation of miR‐148a‐3p/DNMT1 axis

et al. 2016

Cell Biochemistry & Function

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Laryngeal squamous cell carcinoma (LSCC) is a highly aggressive malignant cancer and accounts for 1% to 2% of all malignancies diagnosed worldwide. Runt-related transcription factor 3 (RUNX3), an important tumor suppressor, is known to related to lymph node metastasis and the development of LSCC. However, the biological roles and potential mechanisms RUNX3 expression was not well understood. In this study, we reported that the RUNX3 was significantly downregulated and highly methylated in LSCC compared with their matched normal. The enforced expression of RUNX3 inhibited LSCC cell migration, invasion, and proliferation, whereas the inhibition of RUNX3 did the opposite. We identified that RUNX3 was regulated by miR-148a-3p and found that the expression level of miR-148-3p was significantly decreased and positively related with the expression of RUNX3 in LSCC. We also identified that DNA methyltransferase enzyme DNA (cytosine-5-)-methyltransferase 1 (DNMT1) was targeted by miR-148a-3p in LSCC. The knockdown of DNMT1 promoted the expression of RUNX3 and inhibited migration, invasion, and proliferation in LSCC cells. In summary, our study demonstrated that miR-148a-3p may regulate RUNX3 expression through the modulation of DNMT1-dependent DNA methylation in LSCC, providing a novel target and a potential therapeutic pathway against LSCC. LSCC is a highly aggressive malignant cancer and accounts for 1% to 2% of all malignancies diagnosed worldwide. In this study, we reported that RUNX3, an important tumor suppressor, was significantly downregulated and highly methylated in LSCC compared with their matched normal. The overexpression of RUNX3 inhibited LSCC cell migration, invasion, and proliferation, whereas the inhibition of RUNX3 did the opposite. Moreover, RUNX3 was regulated by miR-148a-3p, which targeted DNA methyltransferase enzyme DNMT1 in LSCC cells. Therefore, miR-148a-3p may regulate RUNX3 expression through the modulation of DNMT1-dependent DNA methylation in LSCC, providing a novel target and a potential therapeutic pathway against LSCC.

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miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

et al. 2015

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B cells undergo affinity maturation and class switch recombination of their immunoglobulin receptors during a germinal center (GC) reaction, before they differentiate into longlived antibody-secreting plasma cells (PCs). Transcription factors such as Bach2 and Mitfare essential during this process, as they delay premature differentiation of GC B cells by repressing Blimp-1 and IRF4, two transcription factors required for terminal PC differentiation. Therefore, Bach2 and Mitf expression must be attenuated in activated B cells to allow terminal PC differentiation, but the precise mechanism remains enigmatic. Here, we provide evidence that miR-148a, a small noncoding microRNA, fosters PC differentiation and survival. Next-generation sequencing revealed that miR-148a is the most abundant microRNA in primary human and murine PCs, and its expression is upregulated in activated murine B cells and coincides with Blimp-1 synthesis. miR-148a targets Bach2, Mitf and proapoptotic factors such as PTEN and Bim. When prematurely expressed, miR-148a promotes the differentiation and survival of plasmablasts and reduces frequencies of IgG1 + cells in primary B-cell cultures. In summary, we propose that miR-148a is a new player in the regulatory network controlling terminal PC differentiation and could, therefore, be a therapeutic target for interfering with PC differentiation and survival.Keywords: B cells r Blimp-1 r MicroRNAs r miR-148a r Plasma cell differentiation r Bach2, Mitf See accompanying article by Haftmann et al.Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe generation of antibody-secreting plasma cells (PCs) and memory B cells is essential for eliminating pathogens and establishing Correspondence: Prof. Hans-Martin Jäck e-mail: hjaeck@molmed.uni-erlangen.de effective protection after vaccination. After antigen encounter, B cells are clonally expanded in the T-cell zone of a peripheral lymphatic organ and differentiate quickly into IgM-secreting short-lived PCs (extrafollicular pathway). If an antigen-activated * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1206-1215 Molecular immunology 1207B cell receives T-cell help, some of these cells move from the Tcell zone to a B-cell follicle located in the B-cell zone. There, they are further expanded, resulting in the formation of a germinal center (GC). During a GC reaction, B cells undergo somatic hypermutation (SHM) of their immunoglobulin variable region exons and class switch recombination (CSR). After B cells with highaffinity and class-switched antigen receptors have been selected, they leave the GC and differentiate either into memory B cells or long-lived PCs [1][2][3]. The differentiation of mature B cells into long-lived PCs via the GC pathway is tightly controlled by a regulatory network of mutually exclusive transcription factors; one set maintains the GC reaction, and the other is re...

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MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in gastric cancer

Cited by 87 publications

References 30 publications

MicroRNA-148a Can Regulate Runt-Related Transcription Factor 3 Gene Expression via Modulation of DNA Methyltransferase 1 in Gastric Cancer

MicroRNA-148a Can Regulate Runt-Related Transcription Factor 3 Gene Expression via Modulation of DNA Methyltransferase 1 in Gastric Cancer

RUNX3 inhibits laryngeal squamous cell carcinoma malignancy under the regulation of miR‐148a‐3p/DNMT1 axis

miR‐148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2

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