Dataset Information

Identification of RASSF1A promoter hypermethylation as a biomarker for hepatocellular carcinoma.

ABSTRACT: Background: RAS association domain family protein 1A (RASSF1A) promoter hypermethylation is suggested to be linked to hepatocellular carcinoma (HCC), but the results remained controversial.

Methods: We evaluated how RASSF1A promoter hypermethylation affects HCC risk and its clinicopathological characteristics through meta-analysis. Data on DNA methylation in HCC and relevant clinical data were also collected based on The Cancer Genome Atlas (TCGA) database to investigate the prognostic role of RASSF1A promoter hypermethylation in HCC.

Results: Forty-four articles involving 4777 individuals were enrolled in the pooled analyses. The RASSF1A promoter methylation rate was notably higher in the HCC cases than the non-tumor cases and healthy individuals, and was significantly related to hepatitis B virus (HBV) infection-positivity and large tumor size. Kaplan-Meier survival analysis revealed that HCC cases with RASSF1A promoter hypermethylation had worse outcomes. Receiver operating characteristic curves confirmed that RASSF1A promoter methylation may be a marker of HCC-related prognoses.

Conclusions: RASSF1A promoter hypermethylation is a promising biomarker for the diagnosis of HCC from tissue and peripheral blood, and is an emerging therapeutic target against HCC.

SUBMITTER: Xu G

PROVIDER: S-EPMC7653745 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of RASSF1A promoter hypermethylation as a biomarker for hepatocellular carcinoma.

Xu Gang G Zhou Xiaoxiang X Xing Jiali J Xiao Yao Y Jin Bao B Sun Lejia L Yang Huayu H Du Shunda S Xu Haifeng H Mao Yilei Y

Cancer cell international 20201110 1

<h4>Background</h4>RAS association domain family protein 1A (RASSF1A) promoter hypermethylation is suggested to be linked to hepatocellular carcinoma (HCC), but the results remained controversial.<h4>Methods</h4>We evaluated how RASSF1A promoter hypermethylation affects HCC risk and its clinicopathological characteristics through meta-analysis. Data on DNA methylation in HCC and relevant clinical data were also collected based on The Cancer Genome Atlas (TCGA) database to investigate the prognos ...[more]

PMID: 33292241

Similar Datasets

Project description:BackgroundSmad interacting protein-1 is a transcription factor that is implicated in transforming growth factor-?/bone morphogenetic protein signaling and a repressor of E-cadherin and human telomerase reverse transcriptase. It is also involved in epithelial-mesenchymal transition and tumorigenesis. However, genetic and epigenetic alterations of SIP1 have not been fully elucidated in cancers. In this study, we investigated mutations and promoter hypermethylation of the SIP1 gene in human hepatocellular carcinomas.MethodsSIP1 expression was analyzed in HCC cell lines and primary tumors in comparison to normal and non-tumor liver tissues by using semi-quantitative RT-PCR, quantitative real-time RT-PCR and immunohistochemistry. Mutation and deletion screening of the SIP1 gene were performed by direct sequencing in HCC-derived cells. Restoration of SIP1 expression was sought by treating HCC cell lines with the DNA methyl transferase inhibitor, 5-AzaC, and the histone deacetylase inhibitor, TSA. SIP1 promoter methylation was analyzed by the combined bisulfite restriction analysis assay in in silico-predicted putative promoter and CpG island regions.ResultsWe found that the expression of SIP1 was completely lost or reduced in five of 14 (36%) HCC cell lines and 17 of 23 (74%) primary HCC tumors. Immunohistochemical analysis confirmed that SIP1 mRNA downregulation was associated with decreased expression of the SIP1 protein in HCC tissues (82.8%). No somatic mutation was observed in SIP1 exons in any of the 14 HCC cell lines. Combined treatment with DNA methyl transferase and histone deacetylase inhibitors synergistically restored SIP1 expression in SIP1-negative cell lines. Analysis of three putative gene regulatory regions revealed tumor-specific methylation in more than half of the HCC cases.ConclusionsEpigenetic mechanisms contribute significantly to the downregulation of SIP1 expression in HCC. This finding adds a new level of complexity to the role of SIP1 in hepatocarcinogenesis.

Project description:Growth arrest DNA damage-inducible gene 45 beta (GADD45beta) has been known to regulate cell growth, apoptotic cell death, and cellular response to DNA damage. Down-regulation of GADD45beta has been verified to be specific in hepatocellular cancer (HCC) and consistent with the p53 mutant, and degree of malignancy of HCC. This observation was further confirmed by eight HCC cell lines and paired human normal and HCC tumor tissues by Northern blot and immunohistochemistry. To better understand the transcription regulation, we cloned and characterized the active promoter region of GADD45beta in luciferase-expressing vector. Using the luciferase assay, three nuclear factor-kappaB binding sites, one E2F-1 binding site, and one putative inhibition region were identified in the proximal promoter of GADD45beta from -865/+6. Of interest, no marked putative binding sites could be identified in the inhibition region between -520/-470, which corresponds to CpG-rich region. The demethylating agent 5-Aza-dC was used and demonstrated restoration of the GADD45beta expression in HepG2 in a dose-dependent manner. The methylation status in the promoter was further examined in one normal liver cell, eight HCC cell lines, eight HCC tissues, and five corresponding nonneoplastic liver tissues. Methylation-specific polymerase chain reaction and sequencing of the sodium bisulfite-treated DNA from HCC cell lines and HCC samples revealed a high percentage of hypermethylation of the CpG islands. Comparatively, the five nonneoplastic correspondent liver tissues demonstrated very low levels of methylation. To further understand the functional role of GADD45beta under-expression in HCC the GADD45beta cDNA constructed plasmid was transfected into HepG2 (p53 WT) and Hep3B (p53 null) cells. The transforming growth factor-beta was assayed by enzyme-linked immunosorbent assay, which revealed a decrease to 40% in transfectant of HepG2, but no significant change in Hep3B transfectant. Whereas, Hep3B co-transfected with p53 and GADD45beta demonstrated significantly reduced transforming growth factor-beta. The colony formation was further examined and revealed a decrease in HepG2-GADD45beta transfectant and Hep3B-p53/GADD45beta co-transfectant. These findings suggested that methylation might play a crucial role in the epigenetic regulation of GADD45beta in hepatocyte transformation that may be directed by p53 status. Thus, our results provided a deeper understanding of the molecular mechanism of GADD45beta down-regulation in HCC.

Dataset Information

Identification of RASSF1A promoter hypermethylation as a biomarker for hepatocellular carcinoma.

Publications

Identification of RASSF1A promoter hypermethylation as a biomarker for hepatocellular carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets