TGF-β1/SMAD3-driven GLI2 isoform expression contributes to aggressive phenotypes of hepatocellular carcinoma
Copyright © 2024 Elsevier B.V. All rights reserved..
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.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2024 |
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Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:588 |
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Enthalten in: |
Cancer letters - 588(2024) vom: 28. Apr., Seite 216768 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Ding, Jia [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 09.04.2024 Date Revised 12.04.2024 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1016/j.canlet.2024.216768 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM369427963 |
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520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Hepatocellular carcinoma | |
650 | 4 | |a Non-canonical hedgehog signaling | |
650 | 4 | |a Recurrence | |
650 | 4 | |a Transforming growth factor-β1 | |
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700 | 1 | |a Yang, Yong-Yu |e verfasserin |4 aut | |
700 | 1 | |a Li, Peng-Tao |e verfasserin |4 aut | |
700 | 1 | |a Ma, Yue |e verfasserin |4 aut | |
700 | 1 | |a Zhang, Li |e verfasserin |4 aut | |
700 | 1 | |a Zhou, Yuan |e verfasserin |4 aut | |
700 | 1 | |a Jin, Cheng |e verfasserin |4 aut | |
700 | 1 | |a Li, Hui-Yan |e verfasserin |4 aut | |
700 | 1 | |a Zhu, Yuan-Fei |e verfasserin |4 aut | |
700 | 1 | |a Liu, Xiu-Ping |e verfasserin |4 aut | |
700 | 1 | |a Liu, Zheng-Jin |e verfasserin |4 aut | |
700 | 1 | |a Jia, Hu-Liang |e verfasserin |4 aut | |
700 | 1 | |a Liu, Ping-Guo |e verfasserin |4 aut | |
700 | 1 | |a Wu, Jian |e verfasserin |4 aut | |
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