RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation.
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Authors
Walsh, NaomiLarkin, AnneMarie
Swan, Niall
Conlon, Kevin
Dowling, Paul
McDermott, Ray
Clynes, Martin
Affiliation
National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland. Naomi.walsh@dcu.ieIssue Date
2011-07-28MeSH
Adenocarcinoma, MucinousBlotting, Western
Carcinoma, Pancreatic Ductal
Cell Adhesion
Cell Movement
Down-Regulation
Gene Expression Regulation, Neoplastic
HSP70 Heat-Shock Proteins
HSP90 Heat-Shock Proteins
Heat-Shock Proteins
Humans
Immunoenzyme Techniques
Immunoprecipitation
Matrix Metalloproteinase 2
Molecular Chaperones
Neoplasm Invasiveness
Pancreatic Neoplasms
RNA, Small Interfering
Tumor Cells, Cultured
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RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation. 2011, 306 (2):180-9 Cancer Lett.Publisher
Cancer lettersJournal
Cancer lettersDOI
10.1016/j.canlet.2011.03.004PubMed ID
21470770Abstract
We previously identified Hop as over expressed in invasive pancreatic cancer cell lines and malignant tissues of pancreatic cancer patients, suggesting an important role for Hop in the biology of invasive pancreatic cancer. Hop is a co-chaperone protein that binds to both Hsp70/Hsp90. We hypothesised that by targeting Hop, signalling pathways modulating invasion and client protein stabilisation involving Hsp90-dependent complexes may be altered. In this study, we show that Hop knockdown by small interfering (si)RNA reduces the invasion of pancreatic cancer cells, resulting in decreased expression of the downstream target gene, matrix metalloproteinases-2 (MMP-2). Hop in conditioned media co-immunoprecipitates with MMP-2, implicating a possible extracellular function for Hop. Knockdown of Hop expression also reduced expression levels of Hsp90 client proteins, HER2, Bcr-Abl, c-MET and v-Src. Furthermore, Hop is strongly expressed in high grade PanINs compared to lower PanIN grades, displaying differential localisation in invasive ductal pancreatic cancer, indicating that the localisation of Hop is an important factor in pancreatic tumours. Our data suggests that the attenuation of Hop expression inactivates key signal transduction proteins which may decrease the invasiveness of pancreatic cancer cells possibly through the modulation of Hsp90 activity. Therefore, targeting Hop in pancreatic cancer may constitute a viable strategy for targeted cancer therapy.Item Type
ArticleLanguage
enISSN
1872-7980ae974a485f413a2113503eed53cd6c53
10.1016/j.canlet.2011.03.004
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