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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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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. |
format | Online Article Text |
id | pubmed-10641234 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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