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 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.

中文翻译：

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TGF-β1/SMAD3驱动的GLI2亚型表达有助于肝细胞癌的侵袭性表型

Hedgehog 信号传导因肝损伤而被激活，并调节器官发生。然而，通过 TGF-β1/SMAD3 进行的非典型刺猬激活在肝癌发生中的作用尚不清楚。在大约一半的 GLI2 阳性肝细胞癌 (HCC) 中发现了 TGF-β1/SMAD3 介导的非典型激活，并鉴定了两种具有反式激活活性的新 GLI2 亚型。 Phospho-SMAD3 与活性 G​​LI2 亚型相互作用，反式激活下游基因，调节低分化肝癌细胞的干性、上皮间质转化、化疗耐药和转移。在转基因 HBV 相关 HCC 小鼠模型中证实了刺猬信号的非典型激活。抑制 TGF-β/SMAD3 信号传导可减少小鼠肝异种移植模型中的肺转移。在另一组 55 名 HCC 患者中，GLI2 高表达的受试者比低表达的受试者无病生存期更短。此外，在 GLI2 高表达的复发性 HCC 患者中，87.5% 观察到 GLI2 与 SMAD3 共阳性，表明 HCC 切除后复发的风险增加。研究结果强调，抑制非典型刺猬信号通路可能为 HCC 的治疗提供一种潜在的策略。