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 ste...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | JHEP Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555923002343 |
| _version_ | 1797435701120204800 |
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| author | Yao Tang Zhijie Xu Fuyuan Xu Juan Ye Jianxu Chen Jianzhong He Yingchun Chen Chunhui Qi Hongbin Huang Ruiyang Liu Hong Shan Fei Xiao |
| author_facet | Yao Tang Zhijie Xu Fuyuan Xu Juan Ye Jianxu Chen Jianzhong He Yingchun Chen Chunhui Qi Hongbin Huang Ruiyang Liu Hong Shan Fei Xiao |
| author_sort | Yao Tang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T10:52:02Z |
| format | Article |
| id | doaj.art-0a4181a3440e484eba2044886ea6a4e9 |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-03-09T10:52:02Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-0a4181a3440e484eba2044886ea6a4e92023-12-01T05:02:48ZengElsevierJHEP Reports2589-55592023-12-01512100903B4GALNT1 promotes hepatocellular carcinoma stemness and progression via integrin α2β1-mediated FAK and AKT activationYao Tang0Zhijie Xu1Fuyuan Xu2Juan Ye3Jianxu Chen4Jianzhong He5Yingchun Chen6Chunhui Qi7Hongbin Huang8Ruiyang Liu9Hong Shan10Fei Xiao11Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, ChinaGuangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, ChinaGuangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, ChinaGuangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, ChinaGuangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, ChinaDepartment of Pathology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, ChinaGuangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, ChinaGuangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, ChinaGuangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, ChinaGuangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, ChinaGuangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Center for Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Corresponding authors. Address: Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 Mei Hua East Road, Zhuhai 51900, Guangdong Province, China. Tel./fax: +86 765 2528527.Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong, China; Kashi Guangdong Institute of Science and Technology, the First People’s Hospital of Kashi, Kashi 844000, Xinjiang, China; Corresponding authors. Address: Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 Mei Hua East Road, Zhuhai 51900, Guangdong Province, China. Tel./fax: +86 765 2528527.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.http://www.sciencedirect.com/science/article/pii/S2589555923002343B4GALNT1ITGB1THBS4Hepatocellular carcinoma |
| spellingShingle | Yao Tang Zhijie Xu Fuyuan Xu Juan Ye Jianxu Chen Jianzhong He Yingchun Chen Chunhui Qi Hongbin Huang Ruiyang Liu Hong Shan Fei Xiao B4GALNT1 promotes hepatocellular carcinoma stemness and progression via integrin α2β1-mediated FAK and AKT activation JHEP Reports B4GALNT1 ITGB1 THBS4 Hepatocellular carcinoma |
| 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 | B4GALNT1 ITGB1 THBS4 Hepatocellular carcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S2589555923002343 |
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