Document Detail


Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma.
MedLine Citation:
PMID:  23041623     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Furthermore, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP.
Authors:
Chad M McKee; Danmei Xu; Yunhong Cao; Sheheryar Kabraji; Danny Allen; Veerle Kersemans; John Beech; Sean Smart; Freddie Hamdy; Adrian Ishkanian; Jenna Sykes; Melania Pintile; Michael Milosevic; Theodorus van der Kwast; Gaetano Zafarana; Varune Rohan Ramnarine; Igor Jurisica; Chad Mallof; Wan Lam; Robert G Bristow; Ruth J Muschel
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-08
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-01     Completed Date:  2013-01-15     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4025-36     Citation Subset:  AIM; IM    
Affiliation:
Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / genetics,  metabolism*,  pathology
Animals
Cell Line, Tumor
Gene Expression Regulation, Neoplastic*
Hedgehog Proteins / genetics,  metabolism*
Humans
Male
Mice
Mice, Knockout
Neoplasm Proteins / genetics,  metabolism*
Neoplasm Transplantation
Neovascularization, Pathologic / genetics,  metabolism,  pathology
Prostatic Neoplasms / genetics,  metabolism*,  pathology
Serpin E2 / biosynthesis*,  genetics
Signal Transduction*
Transplantation, Heterologous
Grant Support
ID/Acronym/Agency:
//Canadian Institutes of Health Research; //Cancer Research UK
Chemical
Reg. No./Substance:
0/Hedgehog Proteins; 0/Neoplasm Proteins; 0/SHH protein, human; 0/Serpin E2; 0/Shh protein, mouse
Comments/Corrections
Comment In:
J Urol. 2013 Jun;189(6):2391   [PMID:  23663646 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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