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B4GALNT1 promotes hepatocellular carcinoma stemness and progression via integrin α2β1-mediated FAK and AKT activation

BACKGROUND & AIMS: β-1,4-N-Acetyl-galactosaminyltransferase 1 (B4GALNT1) has been reported to contribute to the development of human malignancies. However, its role in hepatocellular carcinoma (HCC) remains uncharacterised. In this study, we aimed to elucidate the role of B4GALNT1 in HCC stemnes...

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Autores principales: Tang, Yao, Xu, Zhijie, Xu, Fuyuan, Ye, Juan, Chen, Jianxu, He, Jianzhong, Chen, Yingchun, Qi, Chunhui, Huang, Hongbin, Liu, Ruiyang, Shan, Hong, Xiao, Fei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10641234/
https://www.ncbi.nlm.nih.gov/pubmed/37965158
http://dx.doi.org/10.1016/j.jhepr.2023.100903
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author Tang, Yao
Xu, Zhijie
Xu, Fuyuan
Ye, Juan
Chen, Jianxu
He, Jianzhong
Chen, Yingchun
Qi, Chunhui
Huang, Hongbin
Liu, Ruiyang
Shan, Hong
Xiao, Fei
author_facet Tang, Yao
Xu, Zhijie
Xu, Fuyuan
Ye, Juan
Chen, Jianxu
He, Jianzhong
Chen, Yingchun
Qi, Chunhui
Huang, Hongbin
Liu, Ruiyang
Shan, Hong
Xiao, Fei
author_sort Tang, Yao
collection PubMed
description BACKGROUND & AIMS: β-1,4-N-Acetyl-galactosaminyltransferase 1 (B4GALNT1) has been reported to contribute to the development of human malignancies. However, its role in hepatocellular carcinoma (HCC) remains uncharacterised. In this study, we aimed to elucidate the role of B4GALNT1 in HCC stemness and progression. METHODS: Immunohistochemical staining was used to evaluate B4GALNT1 expression in HCC tissues and adjacent normal liver tissues. Flow cytometry analysis and sphere formation analysis were performed to investigate the role of B4GALNT1 in HCC stemness. Colony formation, Incucyte, wound-healing, Transwell migration, and invasion assays, and an animal model were used to study the role of B4GALNT1 in HCC progression. RNA-sequencing and co-immunoprecipitation were used to investigate the downstream targets of B4GALNT1. RESULTS: B4GALNT1 was upregulated in HCC and associated with poor clinical outcome of patients with the disease. Moreover, B4GALNT1 promoted HCC stemness, migration, invasion, and growth. Mechanistically, B4GALNT1 not only promoted the expression of the integrin α2β1 ligand THBS4, but also directly interacted with the β subunit of integrin α2β1 ITGB1 to inhibit its ubiquitin-independent proteasomal degradation, resulting in activation of FAK and AKT. Ophiopogonin D inhibited HCC stemness and progression by reducing ITGB1 and THBS4 expression and inhibiting FAK and AKT activation. CONCLUSIONS: Our study suggests the B4GALNT1/integrin α2β1/FAK/PI3K/AKT axis as a therapeutic target for the inhibition of HCC stemness and tumour progression. IMPACT AND IMPLICATIONS: The role and regulatory mechanism of B4GALNT1 in HCC have not been studied previously. Here, we reveal that B4GALNT1 has a crucial role in HCC stemness and progression by activating the integrin α2β1/FAK/PI3K/AKT axis, providing a potential target for HCC therapy. In addition, we find Ophiopogonin D as a potential therapeutic drug for patients with HCC.
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spelling pubmed-106412342023-11-14 B4GALNT1 promotes hepatocellular carcinoma stemness and progression via integrin α2β1-mediated FAK and AKT activation Tang, Yao Xu, Zhijie Xu, Fuyuan Ye, Juan Chen, Jianxu He, Jianzhong Chen, Yingchun Qi, Chunhui Huang, Hongbin Liu, Ruiyang Shan, Hong Xiao, Fei JHEP Rep Research Article BACKGROUND & AIMS: β-1,4-N-Acetyl-galactosaminyltransferase 1 (B4GALNT1) has been reported to contribute to the development of human malignancies. However, its role in hepatocellular carcinoma (HCC) remains uncharacterised. In this study, we aimed to elucidate the role of B4GALNT1 in HCC stemness and progression. METHODS: Immunohistochemical staining was used to evaluate B4GALNT1 expression in HCC tissues and adjacent normal liver tissues. Flow cytometry analysis and sphere formation analysis were performed to investigate the role of B4GALNT1 in HCC stemness. Colony formation, Incucyte, wound-healing, Transwell migration, and invasion assays, and an animal model were used to study the role of B4GALNT1 in HCC progression. RNA-sequencing and co-immunoprecipitation were used to investigate the downstream targets of B4GALNT1. RESULTS: B4GALNT1 was upregulated in HCC and associated with poor clinical outcome of patients with the disease. Moreover, B4GALNT1 promoted HCC stemness, migration, invasion, and growth. Mechanistically, B4GALNT1 not only promoted the expression of the integrin α2β1 ligand THBS4, but also directly interacted with the β subunit of integrin α2β1 ITGB1 to inhibit its ubiquitin-independent proteasomal degradation, resulting in activation of FAK and AKT. Ophiopogonin D inhibited HCC stemness and progression by reducing ITGB1 and THBS4 expression and inhibiting FAK and AKT activation. CONCLUSIONS: Our study suggests the B4GALNT1/integrin α2β1/FAK/PI3K/AKT axis as a therapeutic target for the inhibition of HCC stemness and tumour progression. IMPACT AND IMPLICATIONS: The role and regulatory mechanism of B4GALNT1 in HCC have not been studied previously. Here, we reveal that B4GALNT1 has a crucial role in HCC stemness and progression by activating the integrin α2β1/FAK/PI3K/AKT axis, providing a potential target for HCC therapy. In addition, we find Ophiopogonin D as a potential therapeutic drug for patients with HCC. Elsevier 2023-09-05 /pmc/articles/PMC10641234/ /pubmed/37965158 http://dx.doi.org/10.1016/j.jhepr.2023.100903 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Tang, Yao
Xu, Zhijie
Xu, Fuyuan
Ye, Juan
Chen, Jianxu
He, Jianzhong
Chen, Yingchun
Qi, Chunhui
Huang, Hongbin
Liu, Ruiyang
Shan, Hong
Xiao, Fei
B4GALNT1 promotes hepatocellular carcinoma stemness and progression via integrin α2β1-mediated FAK and AKT activation
title B4GALNT1 promotes hepatocellular carcinoma stemness and progression via integrin α2β1-mediated FAK and AKT activation
title_full B4GALNT1 promotes hepatocellular carcinoma stemness and progression via integrin α2β1-mediated FAK and AKT activation
title_fullStr B4GALNT1 promotes hepatocellular carcinoma stemness and progression via integrin α2β1-mediated FAK and AKT activation
title_full_unstemmed B4GALNT1 promotes hepatocellular carcinoma stemness and progression via integrin α2β1-mediated FAK and AKT activation
title_short B4GALNT1 promotes hepatocellular carcinoma stemness and progression via integrin α2β1-mediated FAK and AKT activation
title_sort b4galnt1 promotes hepatocellular carcinoma stemness and progression via integrin α2β1-mediated fak and akt activation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10641234/
https://www.ncbi.nlm.nih.gov/pubmed/37965158
http://dx.doi.org/10.1016/j.jhepr.2023.100903
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