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Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib

Anja Lachenmayer1, Clara Alsinet, Radoslav Savic

  • 1Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY 10029, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 20, 2012
PubMed
Abstract

Insights

Hepatocellular carcinoma (HCC) exhibits active Wnt signaling, classified into CTNNB1 and Wnt-TGFβ molecular subtypes. Sorafenib effectively modulated Wnt signaling in experimental HCC models, showing promise for targeted therapy.

Area of Science:

  • Hepatobiliary cancers
  • Molecular oncology
  • Signal transduction pathways

Background:

  • Hepatocellular carcinoma (HCC) is a heterogeneous malignancy frequently associated with aberrant Wnt signaling.
  • The precise biological mechanisms driving Wnt pathway activation in HCC remain incompletely understood.
  • Current therapeutic strategies lack specific agents targeting the Wnt pathway in HCC.

Purpose of the Study:

  • To comprehensively characterize Wnt pathway aberrations in a cohort of HCC patients.
  • To investigate the potential of sorafenib as a modulator of Wnt signaling in preclinical liver cancer models.

Main Methods:

  • Wnt pathway activity was assessed via mRNA and miRNA expression, immunohistochemistry, and CTNNB1 mutation analysis in HCC samples and cell lines.
  • The impact of sorafenib on Wnt signaling was evaluated in vitro using four HCC cell lines and in vivo using a tumor xenograft model.

Main Results:

  • Nearly half of HCC cases (49.1%) displayed evidence of Wnt activation, categorized into CTNNB1 (21.5%) or Wnt-TGFβ (27.6%) classes.
  • The CTNNB1 class showed nuclear β-catenin and glutamine synthetase expression, while the Wnt-TGFβ class lacked nuclear β-catenin.
  • Sorafenib treatment reduced Wnt signaling and β-catenin levels in HCC cell lines and xenografts, leading to decreased tumor volume and improved survival.

Conclusions:

  • Two distinct Wnt-related molecular subtypes, CTNNB1 and Wnt-TGFβ, characterize approximately half of all HCC patients.
  • Sorafenib demonstrates the capacity to modulate β-catenin and Wnt signaling in experimental models representative of the CTNNB1 HCC subtype.

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