Integrative Array-Based Approach Identifies MZB1 as a Frequently Methylated Putative Tumor Suppressor in Hepatocellular Carcinoma

Matsumura, Satoshi; Imoto, Issei; Kozaki, Ken Ichi; Matsui, Toshimitsu; Muramatsu, Tomoki; Furuta, Mayuko; Tanaka, Shinji; Sakamoto, Michiie; Arii, Shigeki; Inazawa, Johji

doi:10.1158/1078-0432.ccr-11-1007

Cited by 25 publications

(18 citation statements)

References 30 publications

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“…A total of 19 HCC cell lines were maintained in appropriate media as described elsewhere [32]. To examine the restoration of mRNA expression in genes of interest, the cell lines were cultured with or without 5 µM 5-aza-2′-deoxycytidine (5-aza-dCyd) for 5 days and/or 300 nM of TSA for the last 24 hours.…”

Section: Methodsmentioning

confidence: 99%

The Tumor-Suppressive miR-497-195 Cluster Targets Multiple Cell-Cycle Regulators in Hepatocellular Carcinoma

et al. 2013

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MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression and commonly deregulated in carcinogenesis. To explore functionally crucial tumor-suppressive (TS)-miRNAs in hepatocellular carcinoma (HCC), we performed integrative function- and expression-based screenings of TS-miRNAs in six HCC cell lines. The screenings identified seven miRNAs, which showed growth-suppressive activities through the overexpression of each miRNA and were endogenously downregulated in HCC cell lines. Further expression analyses using a large panel of HCC cell lines and primary tumors demonstrated four miRNAs, miR-101, -195, -378 and -497, as candidate TS-miRNAs frequently silenced in HCCs. Among them, two clustered miRNAs miR-195 and miR-497 showed significant growth-suppressive activity with induction of G1 arrest. Comprehensive exploration of their targets using Argonute2-immunoprecipitation-deep-sequencing (Ago2-IP-seq) and genome-wide expression profiling after their overexpression followed by pathway analysis, revealed a significant enrichment of cell cycle regulators. Among the candidates, we successfully identified CCNE1, CDC25A, CCND3, CDK4, and BTRC as direct targets for miR-497 and miR-195. Moreover, target genes frequently upregulated in HCC in a tumor-specific manner, such as CDK6, CCNE1, CDC25A and CDK4, showed an inverse correlation in the expression of miR-195 and miR-497, and their targets. These results suggest the molecular pathway regulating cell cycle progression to be integrally altered by downregulation of miR-195 and miR-497 expression, leading to the aberrant cell proliferation in hepatocarcinogenesis.

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Section: Methodsmentioning

confidence: 99%

The Tumor-Suppressive miR-497-195 Cluster Targets Multiple Cell-Cycle Regulators in Hepatocellular Carcinoma

et al. 2013

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“…In addition, smad signaling is required to maintain epigenetic silencing of some key EMT related proteins in breast cancer progression [22]. Because OCIAD2 frequently methylated in some kinds of cancers [5, 6, 23], we speculate that activated TGF β -Smad signaling provides an epigenetic memory to maintain silencing of OCIAD2 in EMT as well. Thus, disruption of TGF β -Smad4-OCIAD2 signaling may be a useful therapeutic strategy to target tumor progression.…”

Section: Resultsmentioning

confidence: 99%

Pathway Bridge Based Multiobjective Optimization Approach for Lurking Pathway Prediction

Zhang

Zhao

Xiong

et al. 2014

BioMed Research International

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Ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) is a protein with unknown function. Frequently methylated or downregulated, OCIAD2 has been observed in kinds of tumors, and TGFβ signaling has been proved to induce the expression of OCIAD2. However, current pathway analysis tools do not cover the genes without reported interactions like OCIAD2 and also miss some significant genes with relatively lower expression. To investigate potential biological milieu of OCIAD2, especially in cancer microenvironment, a nova approach pbMOO was created to find the potential pathways from TGFβ to OCIAD2 by searching on the pathway bridge, which consisted of cancer enriched looping patterns from the complicated entire protein interactions network. The pbMOO approach was further applied to study the modulator of ligand TGFβ1, receptor TGFβR1, intermediate transfer proteins, transcription factor, and signature OCIAD2. Verified by literature and public database, the pathway TGFβ1- TGFβR1- SMAD2/3- SMAD4/AR-OCIAD2 was detected, which concealed the androgen receptor (AR) which was the possible transcription factor of OCIAD2 in TGFβ signal, and it well explained the mechanism of TGFβ induced OCIAD2 expression in cancer microenvironment, therefore providing an important clue for the future functional analysis of OCIAD2 in tumor pathogenesis.

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“…Since we analyzed a limited number of cell lines for pharmacological unmasking, many other epigenetically inactivated TSGs in HCC still need to be discovered [26,27]. For example, the GSTP1 and RUNX3 genes, which have abnormal methylation in HCCs, were not listed because only 1-2 cell lines out of the 5 HCC cell lines analyzed showed abnormal methylation of these genes [15].…”

Section: Discussionmentioning

confidence: 99%

Identification of Epigenetically Inactivated Genes in Human Hepatocellular Carcinoma by Integrative Analyses of Methylation Profiling and Pharmacological Unmasking

Nishida

Chishina

Arizumi

et al. 2014

Dig Dis

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Objectives: DNA methylation-dependent transcriptional inactivation of tumor suppressor genes (TSGs) is critical for the pathogenesis of hepatocellular carcinoma (HCC). This study identifies potential TSGs in HCCs using methylation profiling and pharmacological unmasking of methylated TSGs. Methods: Methylation profiling was performed on 22 pairs of HCCs and their corresponding noncancerous liver tissues using the Infinium HumanMethylation27 BeadChip. We also determined the gene reexpression after treatment with 5-aza-2′-deoxycytidine (5-Aza-dC) and trichostatin A (TSA) in 5 HCC cell lines. Results: We selected CpGs that exhibited a significant increase in methylation in HCC tissues compared with that of the noncancerous control group. Two hundred and thirteen CpGs on different gene promoters with a mean difference in the β value ≥0.15 and a value of p < 0.05 were selected. Of the 213 genes, 45 genes were upregulated in 3 or more HCC cell lines with multiplier value of differences ≥2.0 after 5-Aza-dC and TSA treatment. Conclusions: We identified several potential TSGs that participate in transcription inactivation through epigenetic interactions in HCC. The results of this study are important for the understanding of functionally important epigenetic alterations in HCC.

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Integrative Array-Based Approach Identifies MZB1 as a Frequently Methylated Putative Tumor Suppressor in Hepatocellular Carcinoma

Cited by 25 publications

References 30 publications

The Tumor-Suppressive miR-497-195 Cluster Targets Multiple Cell-Cycle Regulators in Hepatocellular Carcinoma

The Tumor-Suppressive miR-497-195 Cluster Targets Multiple Cell-Cycle Regulators in Hepatocellular Carcinoma

Pathway Bridge Based Multiobjective Optimization Approach for Lurking Pathway Prediction

Identification of Epigenetically Inactivated Genes in Human Hepatocellular Carcinoma by Integrative Analyses of Methylation Profiling and Pharmacological Unmasking

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