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C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin α(v)

Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related death. Altered glycosylation contributes to tumor progression and chemoresistance in many cancers. C1GALT1 is the key enzyme controlling the elongation of GalNAc-type O-glycosylation. Here we showed that C1GALT1 was overexpressed...

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Autores principales: Kuo, Ting-Chun, Wu, Ming-Hsun, Yang, Shih-Hung, Chen, Syue-Ting, Hsu, Tzu-Wen, Jhuang, Jie-Yang, Liao, Ying-Yu, Tien, Yu-Wen, Huang, Min-Chuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892338/
https://www.ncbi.nlm.nih.gov/pubmed/33420364
http://dx.doi.org/10.1038/s41388-020-01594-4
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author Kuo, Ting-Chun
Wu, Ming-Hsun
Yang, Shih-Hung
Chen, Syue-Ting
Hsu, Tzu-Wen
Jhuang, Jie-Yang
Liao, Ying-Yu
Tien, Yu-Wen
Huang, Min-Chuan
author_facet Kuo, Ting-Chun
Wu, Ming-Hsun
Yang, Shih-Hung
Chen, Syue-Ting
Hsu, Tzu-Wen
Jhuang, Jie-Yang
Liao, Ying-Yu
Tien, Yu-Wen
Huang, Min-Chuan
author_sort Kuo, Ting-Chun
collection PubMed
description Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related death. Altered glycosylation contributes to tumor progression and chemoresistance in many cancers. C1GALT1 is the key enzyme controlling the elongation of GalNAc-type O-glycosylation. Here we showed that C1GALT1 was overexpressed in 85% (107/126) of PDAC tumors compared with adjacent non-tumor tissues. High expression of C1GALT1 was associated with poor disease-free and overall survival (n = 99). C1GALT1 knockdown using siRNA suppressed cell viability, migration, and invasion as well as increased gemcitabine sensitivity in PDAC cells. In contrast, C1GALT1 overexpression enhanced cell migration and invasion. In subcutaneous and pancreatic orthotopic injection models, C1GALT1 knockdown decreased tumor growth and metastasis of PDAC cells in NOD/SCID mice. Mechanistically, C1GALT1 knockdown dramatically suppressed cell-extracellular matrix (ECM) adhesion, which was associated with decreased phosphorylation of FAK at Y397/Y925 and changes in O-glycans on integrins including the β(1), α(v), and α(5) subunits. Using functional blocking antibodies, we identified integrin α(v) as a critical factor in C1GALT1-mediated invasiveness of PDAC cells. In conclusion, this study not only reveals that C1GALT1 could be a potential therapeutic target for PDAC but also provides novel insights into the role of O-glycosylation in the α subunits of integrins.
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spelling pubmed-78923382021-03-03 C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin α(v) Kuo, Ting-Chun Wu, Ming-Hsun Yang, Shih-Hung Chen, Syue-Ting Hsu, Tzu-Wen Jhuang, Jie-Yang Liao, Ying-Yu Tien, Yu-Wen Huang, Min-Chuan Oncogene Article Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related death. Altered glycosylation contributes to tumor progression and chemoresistance in many cancers. C1GALT1 is the key enzyme controlling the elongation of GalNAc-type O-glycosylation. Here we showed that C1GALT1 was overexpressed in 85% (107/126) of PDAC tumors compared with adjacent non-tumor tissues. High expression of C1GALT1 was associated with poor disease-free and overall survival (n = 99). C1GALT1 knockdown using siRNA suppressed cell viability, migration, and invasion as well as increased gemcitabine sensitivity in PDAC cells. In contrast, C1GALT1 overexpression enhanced cell migration and invasion. In subcutaneous and pancreatic orthotopic injection models, C1GALT1 knockdown decreased tumor growth and metastasis of PDAC cells in NOD/SCID mice. Mechanistically, C1GALT1 knockdown dramatically suppressed cell-extracellular matrix (ECM) adhesion, which was associated with decreased phosphorylation of FAK at Y397/Y925 and changes in O-glycans on integrins including the β(1), α(v), and α(5) subunits. Using functional blocking antibodies, we identified integrin α(v) as a critical factor in C1GALT1-mediated invasiveness of PDAC cells. In conclusion, this study not only reveals that C1GALT1 could be a potential therapeutic target for PDAC but also provides novel insights into the role of O-glycosylation in the α subunits of integrins. Nature Publishing Group UK 2021-01-08 2021 /pmc/articles/PMC7892338/ /pubmed/33420364 http://dx.doi.org/10.1038/s41388-020-01594-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kuo, Ting-Chun
Wu, Ming-Hsun
Yang, Shih-Hung
Chen, Syue-Ting
Hsu, Tzu-Wen
Jhuang, Jie-Yang
Liao, Ying-Yu
Tien, Yu-Wen
Huang, Min-Chuan
C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin α(v)
title C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin α(v)
title_full C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin α(v)
title_fullStr C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin α(v)
title_full_unstemmed C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin α(v)
title_short C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin α(v)
title_sort c1galt1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin α(v)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892338/
https://www.ncbi.nlm.nih.gov/pubmed/33420364
http://dx.doi.org/10.1038/s41388-020-01594-4
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