Invasive potential of melanoma cells correlates with the expression of MT1-MMP and regulated by modulating its association with motility receptors via N-glycosylation on the receptors.

Amit Ranjan,Rajiv D Kalraiya

doi:10.1155/2014/804680

Abstract

Matrix remodeling and invasion of basement membrane are the major determinants of malignant progression. Matrix degrading enzymes play a pivotal role in this process and have been shown to be regulated at multiple levels. Using high metastatic B16F10 and its invasive variant B16BL6 cells, we previously demonstrated that the expression of β1,6 branched N-oligosaccharides promotes cellular adhesion on different matrix components which in turn induces secretion of MMP9. The present investigations report that although the two cell lines do not differ in the expression of uPAR, expression of MT1-MMP is significantly higher on B16BL6 cells. Analysis of the transcripts of tissue inhibitors of matrix metalloproteinases (TIMPs) showed that expression of both TIMP1 and TIMP2 correlates negatively with the invasive potential of cells. CD44 and β1 integrin, the two important receptors involved in motility, were identified to carry β1,6 branched N-oligosaccharides in an invasive potential dependent manner. However, their glycosylation status did not appear to influence their surface expression. Although glycosylation on CD44 had no effect, that on β1 integrin significantly affected association of β1 integrin with MT1-MMP. The results thus demonstrate that the cancer cells use multiple mechanisms for degradation of matrix in a controlled manner to couple it with movement for effective invasion.

Highlights

Invasion is a key requirement for malignant progression and remodeling of extracellular matrix is a major component of the invasion process [1]
MT1-matrix metalloproteinases (MMPs) and Urokinase Plasminogen Activation Receptor (uPAR) are the major molecules which are involved in regulating the activity of the MMPs
The expression of uPAR did not correlate with invasiveness (Figure 1(a))

Summary

Introduction

Invasion is a key requirement for malignant progression and remodeling of extracellular matrix is a major component of the invasion process [1]. Cathepsins, serine proteases, and metalloproteinases are the major classes of proteases involved in cancer cell invasion [3] These enzymes are very critical for invasion and metastasis of cells, their expression, activation, and functional properties are tightly regulated. Regulation of matrix degradation by matrix metalloproteinases (MMPs) can occur at several levels such as at the level of (i) basal secretion of MMPs, (ii) induction of their secretion in response to external cues, namely, adhesion to extracellular matrix (ECM) or basement membrane (BM) components, (iii) localization towards invasive front and their activation in the proximity of the invading cell, or (iv) inhibition of their activity by specific metalloproteinase inhibitors like TIMPs [4]. Expression of the metalloproteinases positively correlates with metastatic and invasive potential of several cancers such

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Results

Conclusion