Genome-wide DNA methylation analysis in hepatocellular carcinoma

Yamada, Naotaka; Yasui, Kohichiroh; Dohi, Osamu; Gen, Yasuyuki; Tomie, Akira; Kitaichi, Tomoko; Iwai, Naoharu; Mitsuyoshi, Hironori; Sumida, Yoshio; Moriguchi, Michihisa; Yamaguchi, Kanji; Nishikawa, Taichiro; Umemura, Atsushi; Naito, Yuji; Tanaka, Shinji; Arii, Shigeki; Itoh, Yoshito

doi:10.3892/or.2016.4619

Cited by 52 publications

(44 citation statements)

References 34 publications

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“…These evidences suggested that the broad scope of DNA hypomethylation influenced HCC profoundly and potential biomarkers might be detected from hypomethylated genes. Some hyperm-ethylated promoter genes identified in the current study have been reported in recently published studies, such as TBX15, RASSF10, AKR1B1, CDKL2, and ZNF154 10,13. Consistent with a previous study, S100A8 was presented a lower methylation level in HCC tissues compared to adjacent tissues 22.…”

Section: Discussionsupporting

confidence: 91%

“…Some of the tumor-specific DNA methylations have been proposed to be potential diagnostic or prognostic biomarkers 10,11. Aberrant DNA methylations have been frequently found in HCC, which contributed to carcinogenesis by transcriptional silencing of tumor-suppressor genes (TSGs) 12,13. Recent studies have attempted to find promising epigenetic aberrations to evaluate prognosis 14,15.…”

Section: Introductionmentioning

confidence: 99%

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Aberrant promoter methylation profiles and association with survival in patients with hepatocellular carcinoma

Zhong¹,

Cen²

2017

OTT

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The aim of this study was to investigate the prognostic and diagnostic value of genes with promoter methylation in hepatocellular carcinoma (HCC) patients. On the basis of The Cancer Genome Atlas data, we identified genes with differentially methylated promoters in HCC tissues and adjacent non-tumor tissues, using the linear models for microarray data approach. Cox proportional hazard regression analysis was applied to access the prognostic value of identified differentially methylated genes. The diagnostic value of the genes was evaluated through receiver operating characteristic. Pathway analyses were performed to illustrate biological functions of the identified genes. Compared to adjacent tissues, 77 genes with hypermethylated promoters and 2,412 genes with hypomethylated promoters were identified in HCC. The promoter hypomethylations of RNA5SP38, IL21, SDC4P, and MIR4439 were found to be associated with HCC patient survival (P=0.035, 0.040, 0.004, and 0.024, respectively). Hypomethylated SDC4P was associated with a better prognosis (hazard ratio, 0.482; 95% confidence interval [CI], −0.147–1.110; P=0.007). The combination of the promoter hypomethylations with RNA5SP38, IL21, and SDC4P showed an area under receiver operating characteristic curves of 0.975 (95% CI, 0.962–0.989; P=4.811E-25). Several pathways, including olfactory transduction, cytokine–cytokine receptor interaction, natural killer cell–mediated cytotoxicity, as well as inflammation mediated by chemokine and cytokine signaling pathway, were annotated with the hypomethylated promoter genes. SDC4P promoter hypomethylation may be a potential prognosis biomarker. A panel of promoter methylations in RNA5SP38, IL21, and SDC4P was proven a novel approach to diagnosis HCC. The pathway analysis defined the extensive functional role of DNA hypomethylation in cancer.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Aberrant promoter methylation profiles and association with survival in patients with hepatocellular carcinoma

Zhong¹,

Cen²

2017

OTT

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“…The epigenetic etiology of HCC has been characterized at a genome-wide scale in human tissue and animal models, 17,18,26 whereas much less is known about the role of the epigenome in fatty liver disease and how it may predispose to cancer. In diet-induced fatty liver, potentially compromised function of liverspecific enhancers attributed to elevated 5 mC, in combination with the ubiquitous loss of methylation at other developmentally repressed tissue-specific enhancers, may lead to cell de-differentiation, trans-differentiation, and loss of tissue identity events known to contribute to tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

High fat diet and exercise lead to a disrupted and pathogenic DNA methylome in mouse liver

et al. 2016

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High-fat diet consumption and sedentary lifestyle elevates risk for obesity, non-alcoholic fatty liver disease, and cancer. Exercise training conveys health benefits in populations with or without these chronic conditions. Diet and exercise regulate gene expression by mediating epigenetic mechanisms in many tissues; however, such effects are poorly documented in the liver, a central metabolic organ. To dissect the consequences of diet and exercise on the liver epigenome, we measured DNA methylation, using reduced representation bisulfite sequencing, and transcription, using RNA-seq, in mice maintained on a fast food diet with sedentary lifestyle or exercise, compared with control diet with and without exercise. Our analyses reveal that genome-wide differential DNA methylation and expression of gene clusters are induced by diet and/or exercise. A combination of fast food and exercise triggers extensive gene alterations, with enrichment of carbohydrate/lipid metabolic pathways and muscle developmental processes. Through evaluation of putative protective effects of exercise on diet-induced DNA methylation, we show that hypermethylation is effectively prevented, especially at promoters and enhancers, whereas hypomethylation is only partially attenuated. We assessed diet-induced DNA methylation changes associated with liver cancer-related epigenetic modifications and identified significant increases at liver-specific enhancers in fast food groups, suggesting partial loss of liver cell identity. Hypermethylation at a subset of gene promoters was associated with inhibition of tissue development and promotion of carcinogenic processes. Our study demonstrates extensive reprogramming of the epigenome by diet and exercise, emphasizing the functional relevance of epigenetic mechanisms as an interface between lifestyle modifications and phenotypic alterations.

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“…The methylation of these CpG islands was overall lower in the tumor tissues than in the matched adjacent tissues (Fig. D), with a higher variability between patients in the tumor samples than in the adjacent tissues, suggesting a deregulation of the methylation status in the tumors, as already reported for HCC . To complement these results, miR‐146b‐5p expression levels of 40 HCC tumor tissues, for which both information on the miR‐146b‐5p expression levels and the methylation status was available, were compared to the corresponding adjacent “normal” tissues (Fig.…”

Section: Resultsmentioning

confidence: 57%

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Kirchmeyer

Servais

Hamdorf

et al. 2018

Journal of Leukocyte Biology

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Interleukin-6 (IL-6)-type cytokines play important roles in liver (patho-)biology. For instance, they regulate the acute phase response to inflammatory signals and are involved in hepatocarcinogenesis. Much is known about the regulation of protein-coding genes by cytokines whereas their effects on the miRNome is less well understood. We performed a microarray screen to identify microRNAs (miRNAs) in human hepatocytes which are modulated by IL-6-type cytokines. Using samples of 2 donors, 27 and 68 miRNAs (out of 1,733) were found to be differentially expressed upon stimulation with hyper-IL-6 (HIL-6) for up to 72 h, with an overlap of 15 commonly regulated miRNAs. qPCR validation revealed that miR-146b-5p was also consistently up-regulated in hepatocytes derived from 2 other donors. Interestingly, miR-146b-5p (but not miR-146a-5p) was induced by IL-6-type cytokines (HIL-6 and OSM) in non-transformed liver-derived PH5CH8 and THLE2 cells and in Huh-7 hepatoma cells, but not in HepG2 or Hep3B hepatoma cells. We did not find evidence for a differential regulation of miR-146b-5p expression by promoter methylation, also when analyzing the TCGA data set on liver cancer samples. Inducible overexpression of miR-146b-5p in PH5CH8 cells followed by RNA-Seq analysis revealed effects on multiple mRNAs, including those encoding IRAK1 and TRAF6 crucial for Toll-like receptor signaling. Indeed, LPSmediated signaling was attenuated upon overexpression of miR-146b-5p, suggesting a regulatory loop to modulate inflammatory signaling in hepatocytes. Further validation experiments suggest DNAJC6, MAGEE1, MPHOSPH6, PPP2R1B, SLC10A3, SNRNP27, and TIMM17B to be novel targets for miR-146b-5p (and miR-146a-5p). K E Y W O R D Shepatocarcinogenesis, IL-6-type cytokines, liver, microRNAs, miR-146a-5p steatohepatitis; NF B, nuclear factor kappaB; OSM, oncostatin M; PPP2R1B, protein phosphatase 2 scaffold subunit Abeta; pre-miRNA, precursor-miRNA; pri-miRNA, primary-miRNA; SRPRB, SRP receptor beta subunit; STAT, signal transducer and activator of transcription; TNF , tumor necrosis factor alpha; TRAF6, TNF receptor associated factor 6; TSS, transcription starting site This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Genome-wide DNA methylation analysis in hepatocellular carcinoma

Cited by 52 publications

References 34 publications

Aberrant promoter methylation profiles and association with survival in patients with hepatocellular carcinoma

Aberrant promoter methylation profiles and association with survival in patients with hepatocellular carcinoma

High fat diet and exercise lead to a disrupted and pathogenic DNA methylome in mouse liver

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

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