Tumor cell invasion is the primary reason for morbidity and morality in patients with oral squamous cell carcinomas (OSCC). While it is clear that tumor cell invasion involves extracellular matrix (ECM) components, ECM receptors and proteases, the mechanism remains elusive. The goal of this application is to define the function of laminin-5 (Ln-5) in OSCC tumor invasion. Ln-5 is an ECM component that is proteolytically processed after secretion. Ln-5 has been found in invasive carcinomas and is important in both adhesion and migration of cells. The different proteolytic forms of Ln-5 appear to be responsible for this dual function. We have discovered that OSCC cells synthesize and secrete Ln-5 and that OSCC cells that fail to express processed Ln-5 are invasive while OSCC cells that process Ln-5 are non-invasive. Furthermore, our studies indicate that forced expression of processed Ln-5 in invasive OSCC cells suppresses migration while forced expression of unprocessed Ln-5 in non-invasive OSCC cells increases motility. Finally, we have found that processing of Ln-5 requires procollagen C-proteinase (BMP-1) expression, which is lost in invasive cells. The experiments in this application test the hypothesis that failure to process Ln-5 by BMP-1 leads to weak OSCC adhesion and an increase in OSCC motility and invasion while processing of Ln-5 by BMP-1 leads to stable OSCC adhesion and a reduction in OSCC cell motility and invasion. We will evaluate the expression and processing of Ln-5 and its receptors and assess whether Ln-5 processing influences OSCC migration and invasion. In addition, we will modulate OSCC adhesion, migration and invasion by altering Ln-5 expression and processing and the expression of the Ln-5 receptors. Finally, we will examine the contribution of BMP-1 in processing Ln-5 and determine whether manipulating expression and activity of this protease alters OSCC migration and invasion. This information will help expand our understanding of how the ECM and proteases influence tumor cell invasion in oral cancer. ? ?
| Yuen, Heng-Wai; Ziober, Amy F; Gopal, Pallavi et al. (2005) Suppression of laminin-5 expression leads to increased motility, tumorigenicity, and invasion. Exp Cell Res 309:198-210 |
