Inhibition of Heparanase Expression Results in Suppression of Invasion, Migration and Adhesion Abilities of Bladder Cancer Cells.

Yoshihiro Tatsumi,Satoshi Anai,Makito Miyake,Noboru Konishi,Tomomi Fujii,Kiyohide Fujimoto,Shunta Hori,Yosuke Morizawa,Nobumichi Tanaka,Yasushi Nakai,Keiji Shimada

doi:10.3390/ijms21113789

Yoshihiro Tatsumi, Satoshi Anai + Show 9 more

Open Access

https://doi.org/10.3390/ijms21113789

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Abstract

Heparan sulfate proteoglycan syndecan-1, CD138, is known to be associated with cell proliferation, adhesion, and migration in malignancies. We previously reported that syndecan-1 (CD138) may contribute to urothelial carcinoma cell survival and progression. We investigated the role of heparanase, an enzyme activated by syndecan-1 in human urothelial carcinoma. Using human urothelial cancer cell lines, MGH-U3 and T24, heparanase expression was reduced with siRNA and RK-682, a heparanase inhibitor, to examine changes in cell proliferation activity, induction of apoptosis, invasion ability of cells, and its relationship to autophagy. A bladder cancer development mouse model was treated with RK-682 and the bladder tissues were examined using immunohistochemical analysis for Ki-67, E-cadherin, LC3, and CD31 expressions. Heparanase inhibition suppressed cellular growth by approximately 40% and induced apoptosis. The heparanase inhibitor decreased cell activity in a concentration-dependent manner and suppressed invasion ability by 40%. Inhibition of heparanase was found to suppress autophagy. In N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer mice, treatment with heparanase inhibitor suppressed the progression of cancer by 40%, compared to controls. Immunohistochemistry analysis showed that heparanase inhibitor suppressed cell growth, and autophagy. In conclusion, heparanase suppresses apoptosis and promotes invasion and autophagy in urothelial cancer.

Highlights

Heparan sulfate proteoglycans (HSPGs) are glycoproteins containing heparan sulfate (HS) groups that are covalently attached [1]
We have previously reported that syndecan-1 (CD138) suppresses apoptosis and increases the capacity for cell proliferation via junB-FLIP long signal in urothelial cancer [10]
Heparanase Is Overexpressed in Human Urothelial Carcinoma of the Urinary Bladder, and Heparanase Expression Levels Are Associated with Intravesical Recurrence

Summary

Introduction

Heparan sulfate proteoglycans (HSPGs) are glycoproteins containing heparan sulfate (HS) groups that are covalently attached [1] They are widely expressed and play critical roles in numerous cellular processes, including endocytosis, migration, and adhesion. Their actions are mediated through interactions with ligands such as growth factors, cytokines, extracellular matrix proteins, and enzymes. Syndecan-1 regulates substance permeation and constitutes a reservoir for various growth factors and cytokines in the basement membrane of cells. It plays a critical role in the progression and invasion of urothelial cancer through enhanced angiogenesis

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