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PDIA6 promotes pancreatic cancer progression and immune escape through CSN5-mediated deubiquitination of β-catenin and PD-L1.
- Source :
-
Neoplasia (New York, N.Y.) [Neoplasia] 2021 Sep; Vol. 23 (9), pp. 912-928. Date of Electronic Publication: 2021 Jul 26. - Publication Year :
- 2021
-
Abstract
- Protein Disulfide Isomerase Family A Member 6 (PDIA6) is an endoplasmic reticulum protein that is capable of catalyzing protein folding and disulfide bond formation. Abnormally elevated expression of PDIA6 has been reported to predict poor outcomes in various cancers. Herein, gain-of- and loss-of-function experiments were performed to investigate how PDIA6 participated in the carcinogenesis of pancreatic cancer (PC). By analyzing the protein expression of PDIA6 in 28 paired PC and para carcinoma specimens, we first found that PDIA6 expression was higher in PC samples. Both the overall survival and disease-free survival rates of PC patients with higher PDIA6 expression were poorer than those with lower PDIA6 (n = 178). Furthermore, knockdown of PDIA6 impaired the malignancies of PC cells - suppressed cell proliferation, invasion, migration, cisplatin resistance, and xenografted tumor growth. PDIA6-silenced PC cells were more sensitive to cytotoxic natural killer (NK) cells. Overexpression of PDIA6 had opposite effects on PC cells. Interestingly, COP9 signalosome subunit 5 (CSN5), a regulator of E3 ubiquitin ligases known to promote deubiquitination of its downstream targets, was demonstrated to interact with PDIA6, and its expression was increased in PC cells overexpressing PDIA6. Additionally, PDIA6 overexpression promoted deubiquitination of β-catenin and PD-L1 and subsequently upregulated their expression in PC cells. These alterations were partly reversed by CSN5 shRNA. Collectively, the above results demonstrate that PDIA6 contributes to PC progression, which may be associated with CSN5-regulated deubiquitination of β-catenin and PD-L1. Our findings suggest PDIA6 as a potential target for the treatment of PC.<br /> (Copyright © 2021. Published by Elsevier Inc.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Animals
B7-H1 Antigen genetics
COP9 Signalosome Complex genetics
Deubiquitinating Enzymes genetics
Deubiquitinating Enzymes metabolism
Disease Progression
Female
Humans
Intracellular Signaling Peptides and Proteins genetics
Male
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Neoplasm Grading methods
Pancreatic Neoplasms genetics
Pancreatic Neoplasms immunology
Peptide Hydrolases genetics
Protein Disulfide-Isomerases genetics
beta Catenin genetics
Mice
B7-H1 Antigen metabolism
COP9 Signalosome Complex biosynthesis
Intracellular Signaling Peptides and Proteins biosynthesis
Pancreatic Neoplasms metabolism
Peptide Hydrolases biosynthesis
Protein Disulfide-Isomerases biosynthesis
Tumor Escape physiology
beta Catenin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5586
- Volume :
- 23
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Neoplasia (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 34325342
- Full Text :
- https://doi.org/10.1016/j.neo.2021.07.004