Epigenetic alterations as biomarkers in pancreatic ductal adenocarcinoma

Syren, Pascal; Andersson, Roland; Bauden, Monika; Ansari, Daniel

doi:10.1080/00365521.2017.1301989

Cited by 22 publications

(11 citation statements)

References 52 publications

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“…Unlike the steady increase in survival rates for most cancers, the 5-year survival rate of patients with pancreatic tumors is 8%; furthermore, the 5-year survival rate for patients diagnosed with advanced stages of pancreatic cancer is only 2% [17]. Aberrant DNA methylation in pancreatic tumors has been widely studied in recent years [18, 19], while the relationship between TET1 and pancreatic cancer is still unclear, with only a decrease in 5-hmC levels reported by Yang [20]. In this study, we determined the potential involvement of TET1 in pancreatic cancer progression, focusing on tumor proliferation and metastasis.…”

Section: Introductionmentioning

confidence: 99%

TET1-mediated DNA hydroxymethylation activates inhibitors of the Wnt/β-catenin signaling pathway to suppress EMT in pancreatic tumor cells

Shi

et al. 2019

J Exp Clin Cancer Res

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Background Ten-eleven translocation 1 (TET1) is a dioxygenase that converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) to induce DNA demethylation. TET1 has been reported to be absent in cancers, and to influence various oncogenes and anti-oncogenes. However the function of TET1 in pancreatic tumor remains poorly understood. In this study, we investigated the role of TET1 in the progression of pancreatic tumor and its mechanism of tumor suppression. Methods Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) staining and dot blot were performed to detect the TET1 and 5-hmC expression in pancreatic tumor tissues and its adjacent non-tumor tissues. The clinical parameters significance of pancreatic tumor tissues was determined statistically. TET1 over-expression and knock-out cell lines were built and confirmed in vitro. Cell proliferation assay, wound-healing assays, transwell migration assay and nude mice model of orthotopic pancreatic cancer implantation were performed to assess the function of TET1 in pancreatic tumor. Western blot, qRT-PCR, immunofluorescence (IF), bisulfate sequencing (BSP), Chromatin immunoprecipitation (ChIP) were used to uncover the mechanism. Results TET1 levels and 5-hmC content were downregulated in pancreatic tumor tissues and cell lines, and pancreatic tumor patients with low TET1 levels had a shorter overall survival than patients with high levels of TET1. TET1 suppressed pancreatic tumor proliferation and metastasis in vivo and in vitro. TET1 bound to the secreted frizzled-related protein 2 (SFRP2) promoter and catalyzed demethylation to activate transcription of SFRP2, inhibiting both the canonical and non-canonical Wnt signaling pathways, and ultimately obstructing epithelial-mesenchymal transition (EMT) in pancreatic tumors. Conclusion We found TET1 plays as a suppressor in pancreatic tumor progression via obstructing Wnt signaling pathways. Electronic supplementary material The online version of this article (10.1186/s13046-019-1334-5) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

TET1-mediated DNA hydroxymethylation activates inhibitors of the Wnt/β-catenin signaling pathway to suppress EMT in pancreatic tumor cells

Shi

et al. 2019

J Exp Clin Cancer Res

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“…DNA methylation, post-translational modifications of histone proteins, and non-coding RNAs are the main epigenetic mechanisms that can influence gene expression. They have been confirmed as important contributors to PDAC development and progression [35][36][37].…”

Section: Epigenetic Changes Associated With Pdacmentioning

confidence: 90%

Epigenetic Landscape in Pancreatic Ductal Adenocarcinoma: On the Way to Overcoming Drug Resistance?

Ciernikova

Earl²,

Bermejo³

et al. 2020

IJMS

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies due to the rapid rate of metastasis and high resistance to currently applied cancer therapies. The complex mechanism underlying the development and progression of PDAC includes interactions between genomic, epigenomic, and signaling pathway alterations. In this review, we summarize the current research findings on the deregulation of epigenetic mechanisms in PDAC and the influence of the epigenome on the dynamics of the gene expression changes underlying epithelial–mesenchymal transition (EMT), which is responsible for the invasive phenotype of cancer cells and, therefore, their metastatic potential. More importantly, we provide an overview of the studies that uncover potentially actionable pathways. These studies provide a scientific basis to test epigenetic drug efficacy in synergy with other anticancer therapies in future clinical trials, in order to reverse acquired therapy resistance. Thus, epigenomics has the potential to generate relevant new knowledge of both a biological and clinical impact. Moreover, the potential, hurdles, and challenges of predictive biomarker discoveries will be discussed, with a special focus on the promise of liquid biopsies.

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“…Epigenetic alterations in pancreatic cancer, in particular cell-free DNA and measurement of DNA methylation in pancreatic juice, offers a minimally invasive approach to diagnostics and prognostication. Panels of epigenetic biomarkers have been demonstrated to achieve sensitivities and specificities of 80 to upwards of 90%, however, these studies lack meaningful validation thus precluding their use in routine practice [87,88]. However, recent panels have showed promise for liquid biopsy technology as a pre-diagnostic screening tool for patient with PDAC.…”

Section: Pancreatic Cancermentioning

confidence: 99%

Cancer epigenetics in solid organ tumours: A primer for surgical oncologists

Drake

Søreide

2019

European Journal of Surgical Oncology

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Cancer is initiated through both genetic and epigenetic alterations. The end-effect of such changes to the DNA machinery is a set of uncontrolled mechanisms of cell division, invasion and, eventually, metastasis. Epigenetic changes are now increasingly appreciated as an essential driver to the cancer phenotype. The epigenetic regulation of cancer is complex and not yet fully understood, but application of epigenetics to clinical practice and in cancer research has the potential to improve cancer care. Epigenetics changes do not cause changes in the DNA base-pairs (and, hence, does not alter the genetic code per se) but rather occur through methylation of DNA, by histone modifications, and, through changes to chromatin structure to alter genetic expression. Epigenetic regulators are characterized as writers, readers or erasers by their mechanisms of action. The human epigenome is influenced from cradle to grave, with internal and external life-time exposure influencing the epigenetic marks that may act as modifiers or drivers of carcinogenesis. Preventive and public health strategies may follow from better understanding of the lifetime influence of the epigenome. Epigenetics may be used to define risk, to investigate mechanisms of carcinogenesis, to identify biomarkers, and to identify novel therapeutic options. Epigenetic alterations are found across many solid cancers and are increasingly making clinical impact to cancer management. Novel epigenetic drugs may be used for a more tailored and specific response to treatment of cancers. We present a primer on epigenetics for surgical oncologists with examples from colorectal cancer, breast cancer, pancreatic cancer and hepatocellular carcinoma.

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Epigenetic alterations as biomarkers in pancreatic ductal adenocarcinoma

Cited by 22 publications

References 52 publications

TET1-mediated DNA hydroxymethylation activates inhibitors of the Wnt/β-catenin signaling pathway to suppress EMT in pancreatic tumor cells

TET1-mediated DNA hydroxymethylation activates inhibitors of the Wnt/β-catenin signaling pathway to suppress EMT in pancreatic tumor cells

Epigenetic Landscape in Pancreatic Ductal Adenocarcinoma: On the Way to Overcoming Drug Resistance?

Cancer epigenetics in solid organ tumours: A primer for surgical oncologists

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