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

• Published in: Cancer letters Vol. 588; p. 216768
• Main Authors: Ding, Jia, Yang, Yong-Yu, Li, Peng-Tao, Ma, Yue, Zhang, Li, Zhou, Yuan, Jin, Cheng, Li, Hui-Yan, Zhu, Yuan-Fei, Liu, Xiu-Ping, Liu, Zheng-Jin, Jia, Hu-Liang, Liu, Ping-Guo, Wu, Jian
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.04.2024
• Subjects: Animals; Carcinoma, Hepatocellular - pathology; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Hepatocellular carcinoma; Humans; Liver Neoplasms - pathology; Mice; Mice, Transgenic; Non-canonical hedgehog signaling; Nuclear Proteins - metabolism; Recurrence; Signal Transduction; Smad3 Protein - genetics; Smad3 Protein - metabolism; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-β1; Zinc Finger Protein Gli2 - genetics; Zinc Finger Protein Gli2 - metabolism; Recurrence; Hepatocellular carcinoma; Non-canonical hedgehog signaling; Transforming growth factor-β1
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2024.216768

Hedgehog signaling is activated in response to liver injury, and modulates organogenesis. However, the role of non-canonical hedgehog activation via TGF-β1/SMAD3 in hepatic carcinogenesis is poorly understood. TGF-β1/SMAD3-mediated non-canonical activation was found in approximately half of GLI2-positive hepatocellular carcinoma (HCC), and two new GLI2 isoforms with transactivating activity were identified. Phospho-SMAD3 interacted with active GLI2 isoforms to transactivate downstream genes in modulation of stemness, epithelial-mesenchymal transition, chemo-resistance and metastasis in poorly-differentiated hepatoma cells. Non-canonical activation of hedgehog signaling was confirmed in a transgenic HBV-associated HCC mouse model. Inhibition of TGF-β/SMAD3 signaling reduced lung metastasis in a mouse in situ hepatic xenograft model. In another cohort of 55 HCC patients, subjects with high GLI2 expression had a shorter disease-free survival than those with low expression. Moreover, co-positivity of GLI2 with SMAD3 was observed in 87.5% of relapsed HCC patients with high GLI2 expression, indicating an increased risk of post-resection recurrence of HCC. The findings underscore that suppressing the non-canonical hedgehog signaling pathway may confer a potential strategy in the treatment of HCC. [Display omitted] •Hedgehog signaling transcription factor GLI2 levels correlate with HCC recurrence.•Non-canonical activation by TGF-β/SMAD3 was found in 50% of GLI2-positive HCC samples.•SMAD3 interacted with active GLI2 isoforms to drive HCC progression.•Two newly identified GLI2 isoforms possess transactivating activity.