Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake

Lambert, Marie-Pierre; Paliwal, Anupam; Vaissière, Thomas; Chemin, Isabelle; Zoulim, Fabien; Tommasino, Massimo; Hainaut, Pierre; Sylla, Bakary S.; Scoazec, Jean‐Yves; Tost, Jörg; Herceg, Zdenko

doi:10.1016/j.jhep.2010.07.027

Cited by 155 publications

(140 citation statements)

References 44 publications

Supporting

Mentioning

135

Contrasting

Order By: Relevance

“…Indeed, several frequently methylated genes, such as SLIT2, PTGS2 (COX2), and HHIP, for which methylation data are available in all 3 hepatoma cell lines, showed different methylation patterns among the cell lines (22)(23)(24). These variations may come from the different backgrounds of the 3 cell lines, such as hepatitis B virus infection in Hep3B and no hepatitis virus infection in the other 2 lines, because hypermethylated genes in HCC tumors are known to exhibit remarkably distinct patterns depending on associated risk factors (25,26). Therefore, it is suggested that the candidate genes identified and validated in the present study may contribute to functional pathways shared among different subtypes of HCC regardless of associated risk factors, and this might be the reason why MZB1 protein expression status was not statistically associated with the status of hepatitis virus infection and background liver parenchyma in our analysis.…”

Section: Discussionmentioning

confidence: 99%

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

Matsumura

Imoto

Kozaki

et al. 2012

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: The aim of this study was the identification of novel tumor suppressor genes (TSG) silenced by DNA hypermethylation in hepatocellular carcinoma (HCC).Experimental Design: We conducted integrative array-based approach for genome-wide screening of methylation targets using a methylated DNA immunoprecipitation-CpG island microarray and expression array in three universal hepatoma cell lines and normal liver tissue. Through detailed expression and functional analyses using hepatoma cell lines and primary HCC samples, we isolated novel TSGs for HCC.Results: A total of 642 genes were identified as methylated in three hepatoma cell lines but unmethylated in normal liver tissue, whereas 204 genes on autosomes were identified as genes unexpressed but restored after treatment with 5-aza-2 0 -deoxycytidine in these cell lines and expressed in normal tissue. Through the integration of results of the two-array analyses and further validation analyses of expression and methylation status in 17 cell lines and 30 primary tumors of hepatoma, we identified MZB1, marginal zone B and B1 cellspecific protein, encoding an endoplasmic reticulum protein, as a putative TSG frequently methylated within its CpG island in hepatoma. Among 162 patients with primary HCC, silencing of MZB1 protein was significantly and independently associated with a worse outcome. Restoration of MZB1 expression in hepatoma cells reduced cell proliferation in vitro and in vivo through G 1 -arrest. Conclusions: These results suggest that methylation-mediated silencing of MZB1 expression leads to loss of its tumor-suppressive activity, which may be a factor in the hepatocarcinogenesis, and is a useful prognosticator in HCC.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Matsumura

Imoto

Kozaki

et al. 2012

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…GSTP1 acts as an important tumor suppressor gene, and it is generally accepted that investigation of the hyper-methylation of GSTP1 may elucidate the mechanisms of carcinogenesis (Richiardi et al, 2009). Although the aberrant methylation of GSTP1 has also been described in a substantial proportion of hepatocarcinogenesis cases (Feng et al, 2010;Lambert et al, 2011), details about the mechanisms and significance of DNA hyper-methylation of GSTP1 in HCC are still unknown. The mature GSTP1 protein functions as a detoxifying enzyme, which may play a role in carcinogenesis (Chang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to those environmental risk factors, there is some evidence that genetic factors are also potentially correlated with the progression of HCC (Long et al, 2009;Weng et al, 2010). Recently, several studies have suggested that DNA methylation in the detoxifying genes, including the glutathione S-transferase pi 1 gene (GSTP1), may be closely related to increased risk of HCC (Lambert et al, 2011;Jain et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Abnormal activity and overexpression of GSTP1 have been reported in many neoplasms, while GSTP1 genetic polymorphism and DNA hyper-methylation have also been observed in several cancers, including breast, lung, and liver cancers (Sakoda et al, 2008;Carlsten et al, 2008;Chen et al, 2010). In addition, epigenetic inactivation of GSTP1 may result in the decline or even loss of the detoxification function of GSTP1, and carcinogens can lead to hepatocyte damage; thus, GSTP1 may be closely related to cancer initiation (Lambert et al, 2011). In addition, abnormal CpG island methylation is one of the main molecular mechanisms of GSTP1 inactivation in some types of cancer.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Correlation between promoter methylation in the GSTP1 gene and hepatocellular carcinoma development: a meta-analysis

Qf¹,

Qy²,

Ar³

et al. 2015

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. Epigenetic silencing of the GSTP1 gene by promoter methylation has been associated with increased risk and shortened survival in patients with hepatocellular carcinoma (HCC). We therefore conducted a meta-analysis to obtain a more precise estimate of this association. By searching the Cochrane Library, CBM, EMBASE, PubMed, and the Web of Science, we tabulated and analyzed parameters from each study. Results were summarized by meta-analyses using the version 12.0 STATA software. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were also calculated in this analysis. A total of 14 cohort studies (tumor samples = 607, adjacent samples = 356, benign samples = 182, normal samples = 133) were included for the following statistical analysis. Our meta-analysis results demonstrated that the frequency of GSTP1 methylation in cancer tissues was significantly higher than those in adjacent tissues, benign tissues, and normal tissues (all P < 0.05). Further subgroup analysis by country indicated that the frequency of aberrant GSTP1 promoter methylation was correlated 6763 GSTP1 methylation and HCC ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 6762-6772 (2015) to the development of HCC among all the included experimental subgroups (all P < 0.05). The results indicate a significant association between GSTP1 methylation and poor outcomes in HCC patients.

show abstract

“…Tumor suppressor genes are silenced by hypermethylation in numerous cancer types (14,15). Gene silencing by epigenetic mechanisms, including DNA methylation, has been reported to contribute to HCC development (16)(17)(18). These epigenetic mechanisms, alone or in combination with genetic modifications such as mutations, may lead to the inactivation of tumor suppressor genes, including RASSF1a and APC, and therefore promote hepatocarcinogenesis (19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

DNA methyltransferase 3b silencing affects locus-specific DNA methylation and inhibits proliferation, migration and invasion in human hepatocellular carcinoma SMMC-7721 and BEL-7402 cells

Wang¹,

Wang²,

Fan³

et al. 2015

Oncology Letters

View full text Add to dashboard Cite

Abstract. DNA methylation is an important regulator of gene transcription, and its role in carcinogenesis has been a topic of considerable interest in previous years. The present study examined the influence of DNA methyltransferase 3b (DNMT3b) on cell proliferation, migration and invasion, and the methylation status of identified tumor suppressor genes in hepatoma SMMC-7721 and BEL-7402 cells. DNMT3b was silenced by small interfering RNA (siRNA) in human hepatocellular carcinoma cell lines. Transfection efficiency was verified using a fluorescent imaging system, reverse transcription polymerase chain reaction (RT-PCR) and western blotting. A cell proliferation assay was performed to evaluate cell viability. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The migratory and invasive ability of cells was measured using a Transwell assay. Methylation-specific PCR (MSP) was performed to assess methylation in the promoter region of genes. The present data revealed that DNMT3b siRNA successfully inhibited expression of the DNMT3b gene in these two liver cancer cell lines and therefore inhibited the proliferation of the transfected cells, stimulated apoptosis in the cells, led to an accumulation of cells in the G 2 /M phase and decreased cell migration and invasion. It was also found that silencing DNMT3b expression results in hypomethylation of specific sets of gene promoters and increases the expression of distinct set of genes in HCC cell lines. The present study is therefore useful for assessing the specificity of emerging action based on the altered expression of associated regulatory genes, particularly in methylation-silenced genes.

show abstract

Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake

Cited by 155 publications

References 44 publications

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

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

Correlation between promoter methylation in the GSTP1 gene and hepatocellular carcinoma development: a meta-analysis

DNA methyltransferase 3b silencing affects locus-specific DNA methylation and inhibits proliferation, migration and invasion in human hepatocellular carcinoma SMMC-7721 and BEL-7402 cells

Contact Info

Product

Resources

About