Syndecan-2 Functions as a Docking Receptor for Pro-matrix Metalloproteinase-7 in Human Colon Cancer Cells

Abstract

Although elevated syndecan-2 expression is known to be crucial for the tumorigenic activity in colon carcinoma cells, how syndecan-2 regulates colon cancer is unclear. In human colon adenocarcinoma tissue samples, we found that both mRNA and protein expression of syndecan-2 were increased, compared with the neighboring normal epithelium, suggesting that syndecan-2 plays functional roles in human colon cancer cells. Consistent with this notion, syndecan-2-overexpressing HT-29 colon adenocarcinoma cells showed enhanced migration/invasion, anchorage-independent growth, and primary tumor formation in nude mice, paralleling their morphological changes into highly tumorigenic cells. In addition, our experiments revealed that syndecan-2 enhanced both expression and secretion of matrix metalloproteinase-7 (MMP-7), directly interacted with pro-MMP-7, and potentiated the enzymatic activity of pro-MMP-7 by activating its processing into the active MMP-7. Collectively, these data strongly suggest that syndecan-2 functions as a docking receptor for pro-MMP-7 in colon cancer cells.The characteristics and functions of cancer cells are critically influenced by the actions of cell adhesion receptors, which mediate interactions of cancer cells with the extracellular matrix (ECM) 3 and the cytoskeleton (1). At different points during carcinogenesis, the cell adhesion receptors regulate various cancer cell functions, including cell growth, differentiation, cell survival, angiogenesis, and inflammation (2, 3). Thus, the cancer-specific characteristics and functions of cancer cells are due to the expression and utilization of a distinct set of adhesion receptors that show different expression patterns in normal cells. One group of cancer-related cell adhesion receptors are the syndecans, which are cell surface heparan sulfate proteoglycans known to play diverse roles in cell adhesion and cell communication by serving as co-receptors for both cell signaling and ECM molecules (4). At the plasma membrane, syndecans are capable of transmitting signals from the extracellular environment to the intracellular compartment, thereby regulating adhesion-dependent signal transduction during cell growth (5, 6), cell adhesion and migration (6, 7), cytoskeleton organization (7, 8), and cell differentiation (9). Numerous studies have examined the function of syndecans in various human tumors. Syndecan-1 expression is down-regulated in a great number of squamous cell carcinomas, including uterine cervix, lung, and colorectal cancer (2, 10 -12). However, in other studies, syndecan-1 expression is reportedly up-regulated in prostate, lung, and breast cancers (13-15). In the case of syndecan-2, it has been reported that, in normal tissues, syndecan-2 is expressed in mesenchymal cells but not in normal epithelial cells. However, we found that syndecan-2 expression is increased in several epithelial-driven colon carcinoma cells, and this up-regulation is necessary for the tumorigenic activity of colon carcinoma cells (16). Therefore, it is likely that a...

Sonic hedgehog processing and release are regulated by glypican heparan sulfate proteoglycans

“…This finding is supported by the observed absence of (N-terminal) Shh processing in heparan sulfate-deficient cells and the potentiation of Shh processing by exogenous heparan sulfate in vitro. Hh sheddase activation by heparan sulfate is further consistent with the known increase of Hh solubilization by Suramine, a polysulfated compound (Etheridge et al, 2010) and with Syndecan 2 (another cell surface HSPG) acting as a docking receptor and activator for MMP7 (Ryu et al, 2009). Moreover, ADAM12 associates with HSPGs through its cysteine-rich domain (Iba et al, 2000), and heparan sulfate binding to ADAM12 transiently activates the enzyme (Sorensen et al, 2008).…”

A Unique Phenylalanine in the Transmembrane Domain Strengthens Homodimerization of the Syndecan-2 Transmembrane Domain and Functionally Regulates Syndecan-2

“…Transient transfections were carried out using Vivamagic (Vivagen, Seongnam, Korea), as described in the provided protocol. Monoclonal (mAb) antibody to syndecan-2 (SDC2) was produced by AdipoGen (Incheon, Korea) (19).…”

Syndecans as cell surface receptors: Unique structure equates with functional diversity

“…A recent study reported that syndecan-4 functions in an FGF2-independent manner, further showing that the GAG chains attached to the syndecan-4 core protein are not required for syndecan-4 effects on turkey satellite cell proliferation or initial differentiation (Zhang et al, 2008), although the nature of possible extracellular ligands is unclear. The syndecan-2 core protein appears to directly bind the pro form of matrix metalloproteases-7 (MMP-7) independent of GAG chains (Ryu et al, 2009), and the physiological anti-elastase, α1-antitrypsin, binds to the deglycosylated syndecan-1 core protein but not to glycosylated syndecan-1 (Chan et al, 2009). Recent evidence suggests that the core protein of syndecan-1 can directly interact with β3 integrin (Beauvais et al, 2009).…”