TGF-β1/SMAD3-driven GLI2 isoform expression contributes to aggressive phenotypes of hepatocellular carcinoma

Area of Science:

• Hepatology
• Oncology
• Molecular Biology

Background:

• Hedgehog signaling is crucial for liver development and repair.
• Its role in liver cancer, particularly non-canonical activation via TGF-β1/SMAD3, remains unclear.

Purpose of the Study:

• To investigate the role of non-canonical hedgehog signaling in hepatocellular carcinoma (HCC) pathogenesis.
• To identify therapeutic targets within this pathway.

Main Methods:

• Analysis of GLI2 isoforms and SMAD3 interaction in HCC cells.
• Validation in a transgenic HBV-associated HCC mouse model.
• Assessment of GLI2 and SMAD3 expression in HCC patient cohorts.

Main Results:

• Non-canonical TGF-β1/SMAD3 activation of hedgehog signaling was identified in approximately half of GLI2-positive HCC.
• New GLI2 isoforms with transactivating activity were discovered.
• This pathway promotes stemness, epithelial-mesenchymal transition, chemo-resistance, and metastasis in HCC.
• Inhibition of TGF-β/SMAD3 signaling reduced metastasis in mouse models.
• High GLI2 expression correlated with shorter disease-free survival in HCC patients.
• Co-expression of GLI2 and SMAD3 predicted recurrence risk in relapsed HCC.

Conclusions:

• Non-canonical hedgehog signaling activated by TGF-β1/SMAD3 is a key driver of HCC progression and metastasis.
• Targeting this pathway presents a promising therapeutic strategy for HCC treatment.