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PDIA6 promotes pancreatic cancer progression and immune escape through CSN5-mediated deubiquitination of β-catenin and PD-L1
- Source :
- Neoplasia: An International Journal for Oncology Research, Vol 23, Iss 9, Pp 912-928 (2021), Neoplasia (New York, N.Y.)
- Publication Year :
- 2021
- Publisher :
- Elsevier, 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 />Graphical Abstract Image, graphical abstract
- Subjects :
- Adult
Male
Cancer Research
Protein Disulfide-Isomerases
Mice, Nude
medicine.disease_cause
B7-H1 Antigen
Small hairpin RNA
CSN5
Downregulation and upregulation
Ubiquitin
medicine
Cytotoxic T cell
Animals
Humans
β-catenin signaling pathway
COP9 signalosome
beta Catenin
RC254-282
Original Research
Aged
Aged, 80 and over
Mice, Inbred BALB C
biology
Deubiquitinating Enzymes
Chemistry
COP9 Signalosome Complex
Intracellular Signaling Peptides and Proteins
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Pancreatic cancer
Middle Aged
Pancreatic Neoplasms
PDIA6
Catenin
biology.protein
Cancer research
Disease Progression
Female
Tumor Escape
Neoplasm Grading
Carcinogenesis
Deubiquitination
Peptide Hydrolases
Subjects
Details
- Language :
- English
- ISSN :
- 14765586
- Volume :
- 23
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Neoplasia: An International Journal for Oncology Research
- Accession number :
- edsair.doi.dedup.....1e492ab4c35bf91ab8520d05789938c6