Overexpression of heparanase attenuated TGF‐β‐stimulated signaling in tumor cells. Issue 3 (11th February 2017)

• Record Type: Journal Article
• Authors: Batool, Tahira; Fang, Jianping; Barash, Uri; Moustakas, Aristidis; Vlodavsky, Israel; Li, Jin‐Ping
• Is Part Of: FEBS open bio. Volume 7:Issue 3(2017)
• Page Start: 405
• Page End: 413
• Publication Date: 2017-02-11
• Subjects: cancer cell -- heparan sulfate -- heparanase -- signaling -- TGF‐beta; Molecular biology -- Periodicals; Cytology -- Periodicals; Life sciences -- Periodicals; Biological Science Disciplines -- Periodicals; Molecular Biology -- Periodicals; Cell Biology -- Periodicals; Cytology; Life sciences; Molecular biology; Periodicals; 572.805
• DOI: 10.1002/2211-5463.12190
• Languages: English
• ISSNs: 2211-5463

Abstract

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. Abstract : Heparan sulfate functions as a coreceptor for growth factors, including TGF‐β, affecting the assembly of growth factor–receptor complexes. Heparanase is an endo‐glucuronidase that specifically cleaves and modifies heparan sulfate structure. We found that overexpression of heparanase, through its enzymatic action, attenuated the TGF‐β1‐stimulated Smad, Akt, and Erk phosphorylation and resulted in a slower proliferation of human tumor cells. The results indicate that TGF‐β1 activity is associated with the molecular structure and turnover of heparan sulfate.