title: Overexpression of heparanase attenuated TGF-β-stimulated signaling in tumor cells.
abstract: Heparan sulfate (HS) mediates the activity of various growth factors including TGF-β. Heparanase is an endo-glucuronidase that specifically cleaves and modifies HS structure. In this study, we examined the effect of heparanase expression on TGF-β1-dependent signaling activities. We found that overexpression of heparanase in human tumor cells (i.e., Fadu pharyngeal carcinoma, MCF7 breast carcinoma) attenuated TGF-β1-stimulated Smad phosphorylation and led to a slower cell proliferation. TGF-β1-stimulated Akt and Erk phosphorylation was also affected in the heparanase overexpression cells. This effect involved the enzymatic activity of heparanase, as overexpression of mutant inactive heparanase did not affect TGF-β1 signaling activity. Analysis of HS isolated from Fadu cells revealed an increase in sulfation of the HS that had a rapid turnover in cells overexpressing heparanase. It appears that the structural alterations of HS affect the ability of TGF-β1 to signal via its receptors and elicit a growth response. Given that heparanase expression promotes tumor growth in most cancers, this finding highlights a crosstalk between heparanase, HS, and TGF-β1 function in tumorigenesis.
authors.affiliation: Department of Medical Biochemistry and Microbiology and SciLifeLab University of Uppsala Sweden.
authors.forename: Tahira
authors.initials: T
authors.lastname: Batool
authors.affiliation: Department of Medical Biochemistry and Microbiology and SciLifeLabUniversity of UppsalaSweden; Present address: GlycoNovo Technologies Co., Ltd.ShanghaiChina.
authors.forename: Jianping
authors.initials: J
authors.lastname: Fang
authors.affiliation: Faculty of Medicine Cancer and Vascular Biology Research Center Rappaport Technion Haifa Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Barash
authors.affiliation: Department of Medical Biochemistry and Microbiology and SciLifeLab University of Uppsala Sweden.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
authors.affiliation: Faculty of Medicine Cancer and Vascular Biology Research Center Rappaport Technion Haifa Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Department of Medical Biochemistry and Microbiology and SciLifeLab University of Uppsala Sweden.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
keywords: TGF‐beta; cancer cell; heparan sulfate; heparanase; signaling