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Mimicking and Manipulating Pancreatic Acinar-to-Ductal Metaplasia in 3-dimensional Cell Culture
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Published on: February 11, 2019

Early epigenetic downregulation of WNK2 kinase during pancreatic ductal adenocarcinoma development

C Dutruel1, F Bergmann2, I Rooman3

  • 1Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Oncogene
|August 6, 2013
PubMed

Insights

Epigenetic silencing of the WNK2 gene through hypermethylation is an early event in pancreatic cancer development. This downregulation promotes tumor growth by affecting the ERK-MAPK pathway.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with poorly understood epigenetic mechanisms.
  • Genetic alterations are well-studied, but the role of epigenetic silencing in PDAC pathogenesis remains unclear.

Purpose of the Study:

  • To investigate the contribution of epigenetically silenced genes to PDAC development.
  • To identify specific genes downregulated early in PDAC due to epigenetic alterations.

Main Methods:

  • Analysis of highly methylated DNA from PDAC, chronic pancreatitis (CP), and normal tissues using CpG island microarrays.
  • Investigation of WNK2 in tissue microarrays, methylation analysis of pancreatic intraepithelial neoplasia (PanIN), and PDAC mouse models.
  • Re-expression studies after demethylation and cell growth assays with WNK2 overexpression.

Main Results:

  • WNK2 was identified as a tumor suppressor gene downregulated early in PDAC development.
  • WNK2 hypermethylation was observed in PDAC, CP, PanIN lesions, and a PDAC mouse model.
  • WNK2 downregulation correlated with reduced cell growth and negatively with pERK1/2 expression, suggesting involvement in the ERK-MAPK pathway.

Conclusions:

  • WNK2 promoter hypermethylation is an early event in PDAC pathogenesis.
  • Downregulation of WNK2 contributes to tumor cell proliferation, potentially via the ERK-MAPK pathway.

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