Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; potential marker of disease recurrence

Rengucci, Claudia; Maio, Giulia De; Gardini, A. Caadei; Zucca, Mattia; Scarpi, Emanuela; Zingaretti, Chiara; Foschi, Giovanni; Tumedei, Maria Maddalena; Molinari, Chiara; Saragoni, Luca; Puccetti, Maurizio; Amadori, Dino; Zoli, Wainer; Calistri, Daniele

doi:10.1186/preaccept-1013049468128416

Cited by 7 publications

(7 citation statements)

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“…Chronic inflammation is an important risk factor for cancer development at many sites [ 6 ]. The inflammatory microenvironment exposures induce epigenetic modifications by DNMTs, altering the expression of tumor suppressor genes, which promotes PDAC tumorigenesis and progression [ 7 , 8 ]. As an important member of the tumor inflammatory microenvironment, the pro-inflammatory cytokine IL-6 is involved in pancreatic cancer development [ 9 , 10 ] and directly affects cancer cell growth and survival through activation of STAT3 [ 11 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis

Huang

et al. 2016

J Exp Clin Cancer Res

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BackgroundPrevious studies have investigated the sustained aberrantly activated Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is crucial for pancreatic cancer growth and metastasis. Suppressor of cytokine signaling 3 (SOCS3), as a key negative feedback regulator of this signaling pathway, is usually down-regulated in various cancers. In the present study, we aim at exploring the biological function and the underlying molecular regulation mechanisms of SOCS3 in pancreatic cancer.MethodsThe expression of SOCS3 and other genes in pancreatic cancer was examined by Quantitative real-time PCR, western blotting and immunohistochemical staining. The interaction between pSTAT3 and DNA Methyltransferase 1 (DNMT1) was investigated by co-immunoprecipitation assay. Luciferase reporter assay was used to investigate the transcriptional regulation of pSTAT3 and DNMT1 on the SOCS3 gene. The effects of SOCS3 on the biological behavior of pancreatic cancer cells were assessed both in vitro and vivo. Furthermore, we performed a comprehensive analysis of the expression of SOCS3 in a pancreatic cancer tissue microarray (TMA) and correlated our findings with pathological parameters and outcomes of the patients.ResultsWe showed that SOCS3 expression was decreased in phosphorylated STAT3 (pSTAT3)-positive tumors and was negatively correlated with pSTAT3 in pancreatic cancer cells. We also found that IL-6/STAT3 promoted SOCS3 promoter hypermethylation by increasing DNMT1 activity; silencing DNMT1 or 5-aza-2-deoxycytidine (5-AZA) treatment could reverse the down-regulation of SOCS3 mediated by IL-6. Using co-immunoprecipitation and luciferase reporter assays, we found that STAT3 recruited DNMT1 to the promoter region of SOCS3 and inhibited its transcriptional activity. Overexpression of SOCS3 significantly inhibited cell proliferation, which may be due to the increase in G1-S phase arrest; overexpression of SOCS3 also inhibited cell migration and invasion as well as tumorigenicity in nude mice. Pancreatic cancer tissue microarray analysis showed that high SOCS3 expression was a good prognostic factor and negatively correlated with tumor volume and metastasis.ConclusionWe demonstrated that activated IL-6/STAT3 signaling could induce SOCS3 methylation via DNMT1, which led to pancreatic cancer growth and metastasis. These data also provided a mechanistic link between sustained aberrantly activated IL-6/STAT3 signaling and SOCS3 down-regulation in pancreatic cancer. Thus, inhibitors of STAT3 or DNMT1 may become novel strategies for treating pancreatic cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0301-7) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis

Huang

et al. 2016

J Exp Clin Cancer Res

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“…This seems contradictory to the findings of Rengucci and colleagues who identified the promoters of MLH1, ATM, and FHIT to be hypermethylated in adenomas with high recurrence risk 36. Not determined (N.D.) methylation levels of REV-assay CpG sites are shown as straight lines.…”

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confidence: 73%

Genome‐wide DNA methylation analysis of colorectal adenomas with and without recurrence reveals an association between cytosine‐phosphate‐guanine methylation and histological subtypes

Fiedler

Hirsch

Hajj

et al. 2019

Genes Chromosomes & Cancer

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Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development, which may result in colorectal cancer (CRC). Although gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set of formalin‐fixed paraffin‐embedded colorectal low‐grade adenomas (n = 72) consisting of primary adenomas without and with recurrence (n = 59), recurrent adenomas (n = 10), and normal mucosa specimens (n = 3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome comparing not only primary adenomas without recurrence vs primary adenomas with recurrence but also primary adenomas vs recurrent adenomas using the Illumina Human Methylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with histological adenoma subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5094 DMPs (false discovery rate <0.05; fold change >10%) were identified in the comparisons of recurrent adenomas vs primary adenomas with recurrence (674; 98% hypermethylated), recurrent adenomas vs primary adenomas with and without recurrence (241; 99% hypermethylated) and colorectal adenomas vs normal mucosa (4179; 46% hypermethylated). DMPs in cytosine‐phosphate‐guanine (CpG) islands were frequently hypermethylated, whereas open sea‐ and shelf‐regions exhibited hypomethylation. Gene ontology analysis revealed enrichment of genes associated with the immune system, inflammatory processes, and cancer pathways. In conclusion, our methylation data could assist in establishing a more robust and reproducible histological adenoma classification, which is a prerequisite for improving surveillance guidelines.

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“…Aberrant methylation of the promoter region of ATM has been found to associate with increased radiosensitivity in human CRC cell-line HCT-116 [ 20 ]. Besides, aberrant methylation of ATM was also detected in colorectal cancers and adenomas [ 21 , 22 ]. MET gene encodes a member of the receptor tyrosine kinase family of proteins which regulate various physiological processes including proliferation, morphogenesis and survival, but little is known about its role in CRC.…”

Section: Discussionmentioning

confidence: 99%

Aberrantly methylated-differentially expressed genes and pathways in colorectal cancer

Liu

Sun

et al. 2017

Cancer Cell Int

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BackgroundMethylation plays an important role in the etiology and pathogenesis of colorectal cancer (CRC). This study aimed to identify aberrantly methylated-differentially expressed genes (DEGs) and pathways in CRC by comprehensive bioinformatics analysis.MethodsData of gene expression microarrays (GSE68468, GSE44076) and gene methylation microarrays (GSE29490, GSE17648) were downloaded from GEO database. Aberrantly methylated-DEGs were obtained by GEO2R. Functional and enrichment analyses of selected genes were performed using DAVID database. Protein–protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape. MCODE was used for module analysis of the PPI network.ResultsTotally 411 hypomethylation-high expression genes were identified, which were enriched in biological processes of response to wounding or inflammation, cell proliferation and adhesion. Pathway enrichment showed cytokine–cytokine receptor interaction, p53 signaling and cell cycle. The top 5 hub genes of PPI network were CAD, CCND1, ATM, RB1 and MET. Additionally, 239 hypermethylation-low expression genes were identified, which demonstrated enrichment in biological processes including cell–cell signaling, nerve impulse transmission, etc. Pathway analysis indicated enrichment in calcium signaling, maturity onset diabetes of the young, cell adhesion molecules, etc. The top 5 hub genes of PPI network were EGFR, ACTA1, SST, ESR1 and DNM2. After validation in TCGA database, most hub genes still remained significant.ConclusionIn summary, our study indicated possible aberrantly methylated-differentially expressed genes and pathways in CRC by bioinformatics analysis, which may provide novel insights for unraveling pathogenesis of CRC. Hub genes including CAD, CCND1, ATM, RB1, MET, EGFR, ACTA1, SST, ESR1 and DNM2 might serve as aberrantly methylation-based biomarkers for precise diagnosis and treatment of CRC in the future.

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Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; potential marker of disease recurrence

Cited by 7 publications

References 20 publications

RETRACTED ARTICLE: Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis

RETRACTED ARTICLE: Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis

Genome‐wide DNA methylation analysis of colorectal adenomas with and without recurrence reveals an association between cytosine‐phosphate‐guanine methylation and histological subtypes

Aberrantly methylated-differentially expressed genes and pathways in colorectal cancer

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