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Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma

Claudia Bellomo1,2, Laia Caja1,2, Isabel Fabregat3

  • 1Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-75123, Uppsala, Sweden.

Cell Death and Differentiation
|December 13, 2017
PubMed

Insights

Liver X receptor alpha (LXRα) activation counteracts transforming growth factor beta (TGFβ)-induced mesenchymal changes in liver cancer. LXRα agonists may treat aggressive hepatocellular carcinoma (HCC) dependent on TGFβ.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Hepatocellular carcinoma (HCC) progression involves complex changes in cell differentiation and survival.
  • Transforming growth factor beta (TGFβ) signaling is implicated in promoting apoptosis and mesenchymal transition in HCC.
  • Understanding the interplay between TGFβ and other signaling pathways is crucial for developing novel HCC therapies.

Purpose of the Study:

  • To investigate the crosstalk between transforming growth factor beta (TGFβ) and liver X receptor alpha (LXRα) pathways in hepatocellular carcinoma (HCC).
  • To determine how LXRα activation modulates the cellular responses to TGFβ in HCC.
  • To explore the therapeutic potential of LXRα agonists in aggressive HCC subtypes.

Main Methods:

  • Analysis of signaling pathway crosstalk in HCC cell models.
  • Stimulation of the LXRα receptor system with agonists.
  • Assessment of cellular responses including differentiation, apoptosis, and gene expression.
  • Investigation of the role of the transcription factor Snail in mediating pathway interactions.
  • Examination of LXRα's transcriptional control over the Snail promoter.

Main Results:

  • LXRα activation antagonizes TGFβ-induced mesenchymal differentiation, reactive oxygen species production, and apoptosis in HCC.
  • The mesenchymal transcription factor Snail mediates the crosstalk between LXRα and TGFβ pathways.
  • LXRα activation and TGFβ cooperate to enforce cytostasis, preserving epithelial features in HCC.
  • LXRα transcriptionally regulates Snail expression by acting on the Snail promoter.

Conclusions:

  • LXRα activation offers a mechanism to counteract pro-mesenchymal and pro-apoptotic effects of TGFβ in HCC.
  • The findings highlight a novel role for LXRα in regulating Snail expression and HCC cell fate.
  • Clinically relevant LXRα agonists may represent a therapeutic strategy for aggressive, mesenchymal HCCs driven by TGFβ signaling.

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