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J. Biol. Chem., Vol. 283, Issue 47, 32628-32636, November 21, 2008

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Heparanase Stimulation of Protease Expression Implicates It as a Master Regulator of the Aggressive Tumor Phenotype in Myeloma^*

Anurag Purushothaman, Ligong Chen, Yang Yang, and Ralph D. Sanderson¹

From the Department of Pathology, Center for Metabolic Bone Disease, and the University of Alabama at Birmingham Comprehensive Cancer Center, University of Alabama at Birmingham and the Veterans Administration Medical Center, Birmingham, Alabama 35294

High levels of heparanase are an indicator of poor prognosis in myeloma patients, and up-regulation of the enzyme enhances tumor growth, angiogenesis, and metastasis in animal models. At least part of the impact of heparanase in driving the aggressive tumor phenotype is due to its effect on increasing the expression and shedding of the heparan sulfate proteoglycan syndecan-1, a molecule known to promote myeloma progression. The present work demonstrated that elevation in heparanase expression in myeloma cells stimulates sustained ERK phosphorylation that in turn drives MMP-9 expression. In addition, urokinase-type plasminogen activator (uPA) and uPA receptor expression levels increased, and blocking the proteolytic activation of either MMP-9 or uPA inhibited the heparanase-induced increase in syndecan-1 shedding. Together these data provide a mechanism for heparanase-induced syndecan-1 shedding and, more importantly, demonstrate that heparanase activity in myeloma cells can lead to increased levels of proteases that are known to play important roles in the aggressive behavior of myeloma tumors. This in addition to its other known biological roles, indicates that heparanase acts as a master regulator of the aggressive tumor phenotype by up-regulating protease expression and activity within the tumor microenvironment.

Received for publication, August 13, 2008 , and in revised form, September 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA103054, CA055819, and CA013148 (to R. D. S.). This work was also supported by a VISN7 Research Career Development Award from the Department of Veterans Affairs (to R. D. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology, University of Alabama, 814 SHEL, 1530 Third Ave. S., Birmingham, AL 35294. Tel.: 205-996-6226; Fax: 205-996-6119; E-mail: sanderson{at}uab.edu.

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