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TGF-β induces a decrease in CAPZA1 expression to promote the invasiveness of hepatocellular carcinoma cells.

Le Xiao1, Li Cao2, Zhulin Luo3

  • 1Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, PR China; Department of General Surgery, The General Hospital of Western Theater Command, Chengdu, Sichuan Province 610083, PR China.

The American Journal of the Medical Sciences
|August 12, 2025
PubMed
Summary

Transforming growth factor beta (TGF-β) downregulates CAPZA1 expression by reducing GATA3, which enhances hepatocellular carcinoma (HCC) cell invasiveness. Targeting this TGF-β/GATA3/CAPZA1 pathway inhibits HCC metastasis.

Keywords:
APZA1InvadopodiaInvasivenessTGF-β signaling

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Capza1 (CAPZA1) is underexpressed in hepatocellular carcinoma (HCC), promoting epithelial-mesenchymal transition and F-actin remodeling.
  • The precise role of CAPZA1 in enhancing HCC cell invasiveness and the mechanisms behind its reduced expression remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms driving downregulated CAPZA1 expression in HCC.
  • To investigate the role of CAPZA1 in promoting HCC cell invasiveness.

Main Methods:

  • Investigated TGF-β-induced CAPZA1 downregulation using in vitro and in vivo models.
  • Utilized RNA interference, lentiviral infection, and plasmid transfection to modulate CAPZA1 and GATA3 expression.
  • Confirmed GATA3's transcriptional regulation of CAPZA1 via ChIP assay and evaluated HCC cell invasiveness using FITC-gelatin degradation and invadopodia quantification.

Main Results:

  • CAPZA1 downregulation significantly enhanced HCC cell invasiveness by affecting invadopodia.
  • Identified GATA3 as a key transcription factor regulating CAPZA1, with TGF-β suppressing CAPZA1 via reduced GATA3 expression.
  • SB431542, a TGF-β pathway inhibitor, effectively suppressed HCC metastasis in vivo and CAPZA1 expression in HCC tissues.

Conclusions:

  • TGF-β signaling pathway inhibits GATA3 expression, leading to CAPZA1 downregulation and increased HCC cell invasiveness, likely through invadopodia regulation.
  • Targeting the TGF-β/GATA3/CAPZA1 axis presents a potential therapeutic strategy to inhibit HCC metastasis.