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Updated: Jul 19, 2025

Induction and Analysis of Epithelial to Mesenchymal Transition
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TAp73 Inhibits EMT and Cell Migration in Pancreatic Cancer Cells through Promoting SMAD4 Expression and

Hendrik Ungefroren1,2,3, Björn Konukiewitz1, Rüdiger Braun3

  • 1Institute of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.

Cancers
|August 12, 2023
PubMed

Insights

Transcriptionally active p73 (TAp73) suppresses pancreatic cancer by promoting TGF-β/Smad signaling and inhibiting ERK activation via SMAD4. This TAp73-SMAD4 pathway is crucial for tumor suppression in human pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited treatment options.
  • Transforming growth factor (TGF)-β signaling drives PDAC progression and treatment resistance.
  • The p53 family member, transcriptionally active p73 (TAp73), shows promise in inhibiting tumor progression.

Purpose of the Study:

  • To investigate if the tumor-suppressive mechanism of TAp73 observed in mouse models is applicable to human PDAC.
  • To elucidate the role of TAp73 in regulating TGF-β signaling pathways in human pancreatic cancer cells.

Main Methods:

  • Utilized human PDAC cell lines (PANC-1, HPAFII, L3.6pl).
  • Assessed gene expression of E-cadherin, SMAD4, and SNAIL.
  • Measured basal and TGF-β1-induced activation of extracellular signal-regulated kinases (ERK1/2).
  • Employed SMAD4 inhibition (dominant-negative and RNA interference) and xCELLigence technology for cell migration assays.

Main Results:

  • TAp73 upregulated E-cadherin and SMAD4 while downregulating SNAIL.
  • TAp73 suppressed both basal and TGF-β1-induced ERK1/2 activation.
  • SMAD4 mediated TAp73's inhibition of ERK activation.
  • SMAD4 and TAp73 α-isoform, but not β-isoform, inhibited cell migration.

Conclusions:

  • TAp73-SMAD4 signaling plays a critical role in suppressing human PDAC.
  • TAp73 inhibits pro-invasive ERK activation, both constitutively and upon TGF-β stimulation, through SMAD4.
  • This pathway represents a potential therapeutic target for pancreatic cancer.
Keywords:
PDACSMAD4TAp73cell migrationepithelial-mesenchymal transitiontransforming growth factor-β

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