WD repeat-containing protein 1 maintains β-Catenin activity to promote pancreatic cancer aggressiveness
Open Access
- 15 September 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 123 (6), 1012-1023
- https://doi.org/10.1038/s41416-020-0929-0
Abstract
Background The molecular signature underlying pancreatic ductal adenocarcinoma (PDAC) progression may include key proteins affecting the malignant phenotypes. Here, we aimed to identify the proteins implicated in PDAC with different tumour-node-metastasis (TNM) stages. Methods Eight-plex isobaric tags coupled with two-dimensional liquid chromatography-tandem mass spectrometry were used to analyse the proteome of PDAC tissues with different TNM stages. A loss-of-function study was performed to evaluate the oncogenic roles of WD repeat-containing protein 1 (WDR1) in PDAC. The molecular mechanism by which WDR1 promotes PDAC progression was studied by real-time qPCR, Western blotting, proximity ligation assay and co-immunoprecipitation. Results A total of 5036 proteins were identified, and 4708 proteins were quantified with high confidence. Compared with normal pancreatic tissues, 37 proteins were changed significantly in PDAC tissues of different stages. Moreover, 64 proteins were upregulated or downregulated in a stepwise manner as the TNM stages of PDAC increased, and 10 proteins were related to tumorigenesis. The functionally uncharacterised protein, WDR1, was highly expressed in PDAC and predicted a poor prognosis. WDR1 knockdown suppressed PDAC tumour growth and metastasis in vitro and in vivo. Moreover, WDR1 knockdown repressed the activity of the Wnt/beta-Catenin pathway; ectopic expression of a stabilised form of beta-Catenin restored the suppressive effects of WDR1 knockdown. Mechanistically, WDR1 interacted with USP7 to prevent ubiquitination-mediated degradation of beta-Catenin. Conclusion Our study identifies several previous functional unknown proteins implicated in the progression of PDAC, and provides new insight into the oncogenic roles of WDR1 in PDAC development.Funding Information
- National Natural Science Foundation of China (No.81472221, No.81772566, No.81201896, No.31800691, No.21874026)
This publication has 46 references indexed in Scilit:
- Increased WD-repeat containing protein 1 in interstitial fluid from ovarian carcinomas shown by comparative proteomic analysis of malignant and healthy gynecological tissueBiochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2013
- Recent progress in pancreatic cancerCA: A Cancer Journal for Clinicians, 2013
- Autoantibody against WD repeat domain 1 is a novel serological biomarker for screening of thyroid neoplasiaClinical Endocrinology, 2012
- Wnt/β-Catenin Signaling and DiseaseCell, 2012
- Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progressionProceedings of the National Academy of Sciences of the United States of America, 2010
- FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating AktCancer Cell, 2009
- Wnt/β-Catenin Signaling: Components, Mechanisms, and DiseasesDevelopmental Cell, 2009
- AIP1/WDR1 supports mitotic cell roundingBiochemical and Biophysical Research Communications, 2005
- Disruption of HAUSP gene stabilizes p53Nature, 2004
- Effect of FHIT gene replacement on growth, cell cycle and apoptosis in pancreatic cancer cellsPancreatology, 2003