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Runt-related transcription factor 3 reverses epithelial-mesenchymal transition in hepatocellular carcinoma

Shigetomi Tanaka1, Hidenori Shiraha, Yutaka Nakanishi

  • 1Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.

International Journal of Cancer
|April 11, 2012
PubMed

Insights

Loss of runt-related transcription factor 3 (RUNX3) promotes hepatocellular carcinoma (HCC) progression by inducing epithelial-mesenchymal transition (EMT) via jagged-1 (JAG1) upregulation. Restoring RUNX3 suppresses EMT in HCC cells and tissues.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Runt-related transcription factor 3 (RUNX3) is a tumor suppressor frequently downregulated in hepatocellular carcinoma (HCC).
  • The epithelial-mesenchymal transition (EMT) is a critical process in cancer progression and metastasis, notably in HCC.
  • Understanding RUNX3's role in regulating EMT is crucial for developing targeted HCC therapies.

Purpose of the Study:

  • To elucidate the regulatory mechanism of EMT by RUNX3 in HCC.
  • To investigate the impact of RUNX3 expression on EMT markers in HCC cell lines and tissues.
  • To identify potential molecular pathways, such as jagged-1 (JAG1) signaling, involved in RUNX3-mediated EMT regulation.

Main Methods:

  • Utilized human HCC cell lines (Hep3B, Huh7, HLF, SK-Hep1) classified as low- and high-EMT based on TWIST1 and SNAI2 expression.
  • Performed ectopic RUNX3 expression studies and induced EMT using JAG1 ligand peptide.
  • Conducted immunohistochemical analyses on 33 human HCC tissues and analyzed Oncomine datasets for gene expression correlations.

Main Results:

  • Ectopic RUNX3 expression inhibited EMT in low-EMT HCC cells, increasing E-cadherin and decreasing N-cadherin and vimentin.
  • RUNX3 expression correlated positively with E-cadherin and negatively with N-cadherin and JAG1 in low-EMT HCC tissues and cell lines.
  • JAG1 ligand peptide could re-induce EMT in RUNX3-expressing cells, indicating JAG1's role in RUNX3-mediated EMT suppression.

Conclusions:

  • Loss or decreased RUNX3 expression promotes EMT in low-EMT HCC by inducing JAG1 expression.
  • RUNX3 acts as a suppressor of EMT in HCC, potentially through the JAG1 pathway.
  • These findings reveal a novel mechanism of EMT regulation in HCC and highlight RUNX3 as a potential therapeutic target.

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