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ADAMTS4 and its proteolytic fragments differentially affect melanoma growth and angiogenesis in mice.
MedLine Citation:
PMID:  23319426     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The metalloproteinase ADAMTS4/aggrecanase-1 is highly expressed in cartilage and has been implicated in human arthritis. Although abundantly expressed in many types of cancer, its role in cancer remains unknown. In this work, we demonstrate for the first time that full-length ADAMTS4 or its catalytically more active N-terminal 53 kDa autocatalytic fragment both promote B16 melanoma growth and angiogenesis in mice. In contrast, overexpression of its catalytically-inactive E362A mutant or truncated fragments containing only the C-terminal ancillary domains suppresses melanoma growth and angiogenesis under similar conditions. Structure-function mapping revealed that the single TSR domain is essential and sufficient for the anti-tumorigenic activity displayed by the catalytically-inactive ADAMTS4 isoforms. Suppression of tumor growth and angiogenesis in mice is accompanied by a significant increase in tumor cell apoptosis while tumor cell proliferation is not affected. Importantly, we identified and demonstrated the presence of novel proteolytic fragments of ADAMTS4 containing essentially only the C-terminal ancillary domains in cultured cells, and also in human cancer tissues, co-existing with full-length and catalytically-active N-terminal fragments. The contrasting functions towards tumor growth in mice by the wild-type proteinase and its catalytically-inactive mutant correlate with their contrasting influences on angiogenesis signaling pathway molecules in B16 melanoma in mice. Our results suggest a complex role for ADAMTS4 in cancer with the functional balance of pro-tumorigenic and anti-tumorigenic isoforms likely to act as an important parameter in determining the net influence of this metalloproteinase on tumor growth in vivo. © 2013 Wiley Periodicals, Inc.
Authors:
Nithya Rao; Zhiyuan Ke; Hongrui Liu; Chao-Jin Ho; Saran Kumar; Wei Xiang; Yizhun Zhu; Ruowen Ge
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-15
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  -     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013 UICC.
Affiliation:
Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543.
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