RETRACTED: MMP-9 induces CD44 cleavage and CD44 mediated cell migration in glioblastoma xenograft cells

Abstract

CD44 is implicated in cell-cell and cell-matrix adhesion, cell migration, and signaling. CD44 cleavage correlates with the tumor burden and metastatic potential in various cancers. In this study, we demonstrate that matrix metalloproteinase-9 (MMP-9) acts as a processing enzyme for CD44 cleavage. Further, this processing event stimulates cell motility and inhibition of either CD44 or MMP-9 inhibited cell migration. MMP-9 and CD44 co-localization on the cell surface was observed in the histological sections of human glioblastoma (GBM) tissues. Confocal microscopy and co-immunoprecipitation studies in GBM xenograft cells further confirm this interaction. The interaction of MMP-9 with CD44 induced CD44 cleavage which was inhibited by both transcriptional knockdown of MMP-9 and with MMP-9 specific inhibitor. Further, supplementation of purified and activated human MMP-9 (hMMP-9) in MMP-9-knockdown cells resumed CD44 cleavage and migration. Additionally, activated hMMP-9 protein induced cleavage of recombinant human CD44 (rhCD44) in an in vitro assay. Selective overexpression of either extracellular domain (CD44ECD) or intracellular domain (CD44ICD) confirmed that CD44ECD played a role in cell migration and invasion. Taken together, our results suggest that MMP-9 is involved in the shedding of CD44 from cancer cells, which would promote the malignant potential of tumor cells.

Podoplanin-mediated cell adhesion through extracellular matrix in oral squamous cell carcinoma

“…In the present study, we have demonstrated for the first time that the most fundamental function of PDPN in oral SCC cells is mediating cell adhesion through the crosstalk between CD44 and hyaluronic acid, although its functions had been mainly correlated to cell proliferation 30,31 and migration 32,33 in the literature. The PDPN contribution to cell proliferation has now been shown to be a secondary event to cell adhesion, and the present PDPN inhibition by siRNA did not affect cell migration, as shown in either scratch-wound or transwell migration assays.…”

Emerging insights into the molecular and cellular basis of glioblastoma

“…The immunoglobulin superfamily member CD44 and the hyaluronan-mediated motility receptor (RHAMM), both receptors for hyaluronan, are expressed in glioblastoma (Akiyama et al 2001). CD44 is cleaved by both ADAM proteases (Murai et al 2004) and MMP-9 (Chetty et al 2012) in a process that promotes motility via cytoskeletal reorganization (Murai et al 2004;Bourguignon 2008); it is likely that myosin II is also important for glioma cell contractility during invasion (Beadle et al 2008). Strikingly, CD44 and RHAMM are both suppressed by p53 (Godar et al 2008;Sohr and Engeland 2008), suggesting that early cellular progression through canonical checkpoints and the ability to migrate/invade are linked, although this possibility remains to be validated in glioma models.…”

Expression and inhibitory role of TIMP-3 in hepatocellular carcinoma

“…Furthermore, the balance between MMPs and TIMPs is strongly linked to cellular proliferation, apoptosis, and cell cycle arrest as well as invasion and metastasis (22). The activities of both MMP-2, which can promote αvβ3 integrinmediated adhesion and migration by cleaving fibronectin (23), and MMP-9, which can induce cleavage of the cell-cell/cellmatrix adhesion molecule, CD44 (24), plays an important role in increasing the migration and/or invasion potential of several kinds of cancer cells. Downregulation of the gene that codes for a proliferation-inducing ligand (APRIL), which is typically overexpressed in most tumor cells, leads to reduced expression of MMP-2 and MMP-9 and enhancement of TIMP-3 and TIMP-4 expression (4).…”