DNA methylation status of the SPHK1 and LTB genes underlies the clinicopathological diversity of non-alcoholic steatohepatitis-related hepatocellular carcinomas

Tsuda, Noboru; Tian, Ying; Fujimoto, M. Stanley; Kuramoto, Junko; Makiuchi, Satomi; Ojima, Hidenori; Gotoh, Masahiro; Hiraoka, Nobuyoshi; Yoshida, Teruhiko; Kanai, Yae; Arai, Eri

doi:10.1007/s00432-022-04445-9

Cited by 3 publications

(11 citation statements)

References 47 publications

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“…Many studies have confirmed DNA methylation changed in liver biopsy of patients with NAFLD 45,[47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] (Figure 3). A recent investigation revealed a marked reduction in global DNA methylation among 47 individuals diagnosed with NAFLD compared to a cohort of 18 lean subjects without NAFLD, as assessed via liver biopsy.…”

Section: Clinical Researchmentioning

confidence: 95%

“…112 Inappropriate binding of DNA methyltransferase to unrepaired damage or mismatches may promote local histone deacetylation, methylation, and regional hypermethylation, leading to tumour suppressor gene silencing. 64,98,113 The low FA may lead to a compensatory increase of MTHFR. HCC cancer patients with higher MTHFR had a worse survival rate.…”

Section: Appropriate Folic Acid May Prevent Tumour Formation and Prog...mentioning

confidence: 99%

“…The mechanism underlying the association between low FA and cancer may involve FA depletion leading to increased DNA strand breaks, uridine malformation, and repair defects, resulting in chromosome instability 112 . Inappropriate binding of DNA methyltransferase to unrepaired damage or mismatches may promote local histone deacetylation, methylation, and regional hypermethylation, leading to tumour suppressor gene silencing 64,98,113 . The low FA may lead to a compensatory increase of MTHFR.…”

Section: Folic Acid and Cancermentioning

confidence: 99%

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The relationship between folic acid and nonalcoholic fatty liver disease

Xu,

Yang,

Zhu

et al. 2024

Clinical and Translational Dis

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In recent years, the incidence of non‐alcoholic fatty liver disease (NAFLD) has been increasing, which has become an explosive interest because of the growing impact on world health. NAFLD is the hepatic manifestation of systemic metabolic syndrome (MS), and the umbrella term that comprises a continuum of liver conditions, from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and hepatocellular carcinoma (HCC). currently, there is no pharmacological agent that is therapeutically approved for the treatment of this disease. Folic acid (FA) was one of a water‐soluble B vitamins, entirely absorbed from the diet. Numbers of clinical studies have confirmed that patients with NAFLD and insulin resistance are often accompanied by abnormal FA. We investigated the potential effects of FA on NAFLD through the metabolic pathways, DNA synthesis and methylation, oxidative stress in liver and intestinal flora. In addition, FA has an effect on HCC or other cancer. Therefore, FA might be a safe and economical potential treatment method for NAFLD.

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Section: Clinical Researchmentioning

confidence: 95%

Section: Appropriate Folic Acid May Prevent Tumour Formation and Prog...mentioning

confidence: 99%

Section: Folic Acid and Cancermentioning

confidence: 99%

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The relationship between folic acid and nonalcoholic fatty liver disease

Xu,

Yang,

Zhu

et al. 2024

Clinical and Translational Dis

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“…Infinium data for 25 NASH-Ns, 25 NASH-Ts, 37 V-Ns, 37 V-Ts, and 36 NLTs were also included in our previous papers focusing on NASH-related hepatocarcinogenesis: 29 U-Ns, 29 U-Ts, 16 AL-Ns, and 16 AL-Ts (90 samples in total) were originally examined for this study. [13][14][15][16]…”

Section: Infinium Assaymentioning

confidence: 99%

“…DNA hypomethylation resulting in increased expression of the SPHK1 and LTB genes in poorly differentiated HCCs may underlie the aggressive phenotype of such HCCs. 15 Moreover, we have identified tumor-related genes, such as WHSC1, 13 TRIM4, PRC1, and TUBA1B, 16 whose expression levels are regulated by DNA methylation status, as potential therapeutic targets in NASH-related HCCs.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation alterations of ADCY5, MICAL2, and PLEKHG2 during the developmental stage of cryptogenic hepatocellular carcinoma

Makiuchi,

Tian,

Fujimoto

et al. 2023

Hepatology Research

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AimThe aim of this study was to clarify the significance of DNA methylation alterations of cryptogenic hepatocellular carcinomas (HCCs).MethodsUsing the Infinium assay, we performed genome‐wide DNA methylation analysis of 250 liver tissue samples, including non‐cancerous liver tissue (U‐N) and corresponding cancerous tissue (U‐T) from patients with cryptogenic HCC without a history of excessive alcohol use and hepatitis virus infection, and whose U‐N samples showed no remarkable histological features (no microscopic evidence of simple steatosis, any form of hepatitis including non‐alcoholic steatohepatitis [NASH], or liver cirrhosis).ResultsWe identified 3,272 probes that showed significant differences of DNA methylation levels between U‐N and normal liver tissue samples from patients without HCC, indicating that a distinct DNA methylation profile had already been established at the precancerous U‐N stage. U‐Ns have a DNA methylation profile differing from that of non‐cancerous liver tissue of patients with NASH‐related, viral hepatitis‐related, and alcoholic liver disease‐related HCCs. Such DNA methylation alterations in U‐Ns were inherited by U‐Ts. The U‐Ns showed DNA methylation alteration of ADCY5 resulting in alteration of its mRNA expression, whereas non‐cancerous liver tissue of patients with NASH‐, viral hepatitis‐, or alcoholic liver disease‐related HCCs did not. DNA methylation levels of MICAL2 and PLEKHG2 in U‐Ts were correlated with larger tumor diameter and portal vein involvement, respectively.ConclusionsU‐N‐specific DNA hypermethylation of ADCY5 may have significance even from the precancerous stage in liver showing no remarkable histological features. DNA hypomethylation of MICAL2 and PLEKHG2 may determine the clinicopathological features of cryptogenic HCC.This article is protected by copyright. All rights reserved.

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Molecular pathological approach to cancer epigenomics and its clinical application

Kanai

2024

Pathology International

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Careful microscopic observation of histopathological specimens, accumulation of large numbers of high‐quality tissue specimens, and analysis of molecular pathology in relation to morphological features are considered to yield realistic data on the nature of multistage carcinogenesis. Since the morphological hallmark of cancer is disruption of the normal histological structure maintained through cell−cell adhesiveness and cellular polarity, attempts have been made to investigate abnormalities of the cadherin‐catenin cell adhesion system in human cancer cells. It has been shown that the CDH1 tumor suppressor gene encoding E‐cadherin is silenced by DNA methylation, suggesting that a “double hit” involving DNA methylation and loss of heterozygosity leads to carcinogenesis. Therefore, in the 1990s, we focused on epigenomic mechanisms, which until then had not received much attention. In chronic hepatitis and liver cirrhosis associated with hepatitis virus infection, DNA methylation abnormalities were found to occur frequently, being one of the earliest indications that such abnormalities are present even in precancerous tissue. Aberrant expression and splicing of DNA methyltransferases, such as DNMT1 and DNMT3B, was found to underlie the mechanism of DNA methylation alterations in various organs. The CpG island methylator phenotype in renal cell carcinoma was identified for the first time, and its therapeutic targets were identified by multilayer omics analysis. Furthermore, the DNA methylation profile of nonalcoholic steatohepatitis (NASH)‐related hepatocellular carcinoma was clarified in groundbreaking studies. Since then, we have developed diagnostic markers for carcinogenesis risk in NASH patients and noninvasive diagnostic markers for upper urinary tract cancer, as well as developing a new high‐performance liquid chromatography‐based diagnostic system for DNA methylation diagnosis. Research on the cancer epigenome has revealed that DNA methylation alterations occur from the precancerous stage as a result of exposure to carcinogenic factors such as inflammation, smoking, and viral infections, and continuously contribute to multistage carcinogenesis through aberrant expression of cancer‐related genes and genomic instability. DNA methylation alterations at the precancerous stages are inherited by or strengthened in cancers themselves and determine the clinicopathological aggressiveness of cancers as well as patient outcome. DNA methylation alterations have applications as biomarkers, and are expected to contribute to diagnosis, as well as preventive and preemptive medicine.

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DNA methylation status of the SPHK1 and LTB genes underlies the clinicopathological diversity of non-alcoholic steatohepatitis-related hepatocellular carcinomas

Cited by 3 publications

References 47 publications

The relationship between folic acid and nonalcoholic fatty liver disease

The relationship between folic acid and nonalcoholic fatty liver disease

DNA methylation alterations of ADCY5, MICAL2, and PLEKHG2 during the developmental stage of cryptogenic hepatocellular carcinoma

Molecular pathological approach to cancer epigenomics and its clinical application

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