Abstract

Malignant pleural mesothelioma (MPM) is a neoplasm arising from the mesothelial cells that line the thoracic pleura. Many factors such as asbestos, genetic predisposition, Simian Virus 40 (SV40) and radiation have been linked to MPM. Although, roles of osteonectin (SPARC) in various cancers including peritoneal MM have previously been studied, its involvement in development of MPM remains to be established. Our RT-PCR and Western blot analysis revealed elevated levels of osteonectin in archived MPM compared to normal peritoneum. We next generated Osteonectin-expressing stable cell lines derived from immortalized mesothelial Met5A cells. In addition, osteonectin expression was knocked-down by stable expression of osteonectin antisense in a patient-derived MPM cell line H2714. The osteonectin-expressing Met5A cells elicited faster migration rates when compared with their vector-expressing controls. Depletion of osteonectin, on the other hand, resulted in a slower migration rate of the MPM cells when compared with their vector-expressing counterparts. Expression of osteonectin also resulted in increased adhesion of the Met5A cells to collagen I, fibronectin and Laminin-coated plates while their adhesion to the collagen IV coated plates was decreased. Interestingly, knock-down of Osteonectin in MPM cells failed to influence their adhesion properties. Finally, we conducted in vitro invasion assays to determine whether osteonectin expression modulated invasive properties of these cells. Osteonectin expression in Met5A cells resulted in significant increase in their invasive properties while loss of osteonectin in MPM cells interfered with their abilities to invade. Taken together, our studies demonstrate that osteonectin regulates MPM cell adhesion, migration, and invasion properties, and therefore is an important regulator of MPM development and progression.

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