DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment

Conemans, Elfi B.; Lodewijk, Lutske; Moelans, Cathy B.; Offerhaus, G. Johan A.; Pieterman, Carolina R. C.; Morsink, Folkert H.M.; Dekkers, Olaf M.; Herder, Wouter W. de; Hermus, A.R.M.M.; Horst-Schrivers, Anouk N. van der; Drent, Madeleine L.; Bisschop, Peter H.; Havekes, Bas; Brosens, Lodewijk A.A.; Dreijerink, Koen M.A.; Rinkes, Inne H.M. Borel; Timmers, H. Th. Marc; Valk, Gerlof D.; Vriens, Menno R.

doi:10.1530/eje-18-0195

Cited by 29 publications

(39 citation statements)

References 40 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…DNA hypermethylation has an important role in PanNET tumorigenesis and should be further studied to potentially identify novel therapeutic targets (Conemans et al 2018, Tirosh et al 2019. Additional inquiries included the exploration of possible immunotherapybased interventions to prevent metastases or PanNET.…”

Section: Discussionmentioning

confidence: 99%

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: MEN1-related pancreatic NETs: identification of unmet clinical needs and future directives

Pieterman

Sadowski

Maxwell

et al. 2020

Endocrine-Related Cancer

Self Cite

View full text Add to dashboard Cite

The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27–29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.

show abstract

“…Higher global DNA hypermethylation was detected in non-functional PNETs from MEN1 patients in comparison with sporadic and VHL-associated PNETs ( 71 ). Also, promoter hypermethylation was observed as a frequent event in MEN1-associated advanced PNETs ( 72 ). Validation of these findings in independent cohorts of familial and sporadic PNETs will help to determine the importance of DNA methylation as a biomarker.…”

Section: Molecular Mechanisms and Prognosis In Pnetsmentioning

confidence: 99%

Molecular Signatures and Their Clinical Utility in Pancreatic Neuroendocrine Tumors

2021

View full text Add to dashboard Cite

Pancreatic neuroendocrine tumors (PNETs) are classified based on their histologic differentiation and proliferative indices, which have been used extensively to determine prognosis. Advances in next-generation sequencing and other high-throughput techniques have allowed researchers to objectively explore tumor specimens and learn about the genetic alterations associated with malignant transformation in PNETs. As a result, targeted, pathway-specific therapies have been emerging for the treatment of unresectable and metastatic disease. As we continue to trial various pharmaceutical products, evidence from studies using multi-omics approaches indicates that clinical aggressiveness stratifies along other genotypic and phenotypic demarcations, as well. In this review, we explore the clinically relevant and potentially targetable molecular signatures of PNETs, their associated trials, and the overall differences in reported prognoses and responses to existing therapies.

show abstract

DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment

Abstract: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

Cited by 29 publications

References 40 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

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: MEN1-related pancreatic NETs: identification of unmet clinical needs and future directives

Molecular Signatures and Their Clinical Utility in Pancreatic Neuroendocrine Tumors

Contact Info

Product

Resources

About