Overexpression of heparanase attenuated TGF-β-stimulated signaling in tumor cells.

Tahira Batool,Uri Barash,Aristidis Moustakas,Jin‐Ping Li,Israel Vlodavsky,Jianping Fang

doi:10.1002/2211-5463.12190

Tahira Batool, Uri Barash + Show 4 more

Open Access

https://doi.org/10.1002/2211-5463.12190

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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.

Highlights

Heparan sulfate (HS) mediates the activity of various growth factors including TGF-b
transforming growth factor beta 1 (TGF-b1) induced phosphorylation of Smad, Akt, and ERK is attenuated in cancer cells overexpressing heparanase
The results show that stimulation with TGF-b1 led to phosphorylation of Smad2 in Fadu cells essentially in a dose-dependent manner up to a concentration of 5 ngÁmLÀ1 TGF-b1 (Fig. 1B)

Summary

Introduction

Heparan sulfate (HS) mediates the activity of various growth factors including TGF-b. 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-b1 to signal via its receptors and elicit a growth response. One of the important functions of HSPG is to mediate growth factor-stimulated cell signaling, through interaction of the heparan sulfate (HS) side chains with growth factors and their receptors [4]. Heparanase is an endo-glucuronidase that modifies HS structure through cleavage of the long HS polysaccharide chains to shorter fragments This unique mammalian enzyme is expressed at essentially nondetectable amounts in normal tissues, but is elevated in a number of pathological conditions such as cancer and inflammation [7,8], indicating that the enzyme has important functions in pathophysiology.

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