A CRITICAL ROLE FOR GELSOLIN IN COLORECTAL CANCER CELL DISSEMINATION

Abstract

Gelsolin is a cytoskeletal protein which participates in actin filament dynamics and promotes cell plasticity and motility. While the role of gelsolin in cytoskeleton remodelling is well-established, its function in tumor biology is controversial. Various studies have implicated gelsolin as a tumor suppressor, based mainly from observations of gelsolin downregulation in tumors. Nevertheless, the re-emergence of gelsolin in certain tumors correlates with poor prognosis and therapy-resistance. Gelsolin has also been reported to confer pro-migratory, pro-invasive and anti-apoptotic effects in tumor cells, suggesting a tumor enhancer role. The conflicting evidence suggests that the role of gelsolin in tumor biology is complex, and possibly gelsolin may be required to accelerate cancer progression in more advanced disease. Thus far, the pro-disseminative roles of gelsolin as well as the mechanisms involved are unclear. We investigated the influence of gelsolin on the invasive activity of colorectal cancer cells. Using overexpression and small interfering RNA knockdown, we show that gelsolin is required for invasion of colorectal cancer cells through matrigel in transwell assays. Microarray analysis and quantitative PCR indicate that gelsolin overexpression induces the upregulation of invasion-promoting genes in colorectal cancer cells, including urokinase plasminogen activator (uPA) whilst gelsolin knockdown reduces uPA levels. The enhanced invasiveness of gelsolin-overexpressing cells could be attenuated by treatment with function-blocking antibodies to either uPA or uPAR, indicating that uPA/uPAR activity is crucial for gelsolin-dependent invasion. Furthermore, in over 25% of colorectal cancer liver metastases examined by immunohistochemistry, gelsolin was highly expressed at tumor borders infiltrating into adjacent liver tissues. Interestingly, increased gelsolin in colorectal cancer cells induced a loss of epithelial cell morphology, resulting in a scattered appearance, while downregulation of gelsolin reversed cell scattering. These oncogenic changes suggest that gelsolin induces various cooperative mechanisms to promote tumor cell dissemination. In summary, our novel findings support a critical role for gelsolin in colorectal cancer dissemination, through the induction of cell invasion and cell scattering. Our findings would contribute to a greater understanding of the malignant transformation process in colorectal cancer cells.