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C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin ?_v.

ABSTRACT: 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 ?₁, ?_v, and ?₅ subunits. Using functional blocking antibodies, we identified integrin ?_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 ? subunits of integrins.

SUBMITTER: Kuo TC

PROVIDER: S-EPMC7892338 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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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<sub>v</sub>.

Kuo Ting-Chun TC Wu Ming-Hsun MH Yang Shih-Hung SH Chen Syue-Ting ST Hsu Tzu-Wen TW Jhuang Jie-Yang JY Liao Ying-Yu YY Tien Yu-Wen YW Huang Min-Chuan MC

Oncogene 20210108 7

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 ...[more]

PMID: 33420364

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Project description:Pancreatic ductal adenocarcinoma (PDAC) remains a major cause of cancer-associated mortality, with poor patient outcome. The present study aimed to identify key candidate genes and investigate the potential molecular mechanisms associated with the progression of PDAC. The GSE46234 dataset was downloaded from the Gene Expression Omnibus database, in order to identify the upregulated differentially expressed genes (DEGs) in PDAC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine the biological functions and pathways of the upregulated DEGs, and a protein-protein interaction (PPI) network was subsequently constructed to screen the hub genes. Subsequently, survival analyses of the hub genes were undertaken in patients with PDAC, using The Cancer Genome Atlas dataset. Reverse transcription-quantitative (RT-q)PCR analysis was performed to assess the mRNA expression levels of the hub genes associated with the prognosis of patients with PDAC. In the present study, 65 upregulated DEGs were identified. GO analysis suggested that the DEGs were enriched in response to hypoxia, calcium ion and negative regulation of catecholamine. KEGG analysis demonstrated that the DEGs were enriched in gastric acid secretion, the ECM-receptor interaction and the cGMP-PKG signaling pathway. Among the 18 hub genes determined by module screening of the PPI network, upregulation of three key genes, abnormal spindle-like microcephaly-associated protein (ASPM), mitotic checkpoint serine/threonine-protein kinase BUB1 ? (BUB1B) and protein spindly (SPDL1), was significantly associated with worse overall survival and disease-free survival time in patients with PDAC. Furthermore, ASPM, BUB1B and SPDL1 were demonstrated to be associated with advanced tumor stage, and their upregulation in PDAC tumor tissues was validated using RT-qPCR analysis. Taken together, the results of the present study demonstrate that ASPM, BUB1B and SPDL1 may have the potential to function as prognostic markers and therapeutic targets for PDAC.

Dataset Information

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

Publications

C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin α<sub>v</sub>.

Similar Datasets

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C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin ?_v.