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Overexpression of the Calcium Sensor Visinin-like Protein-1 Leads to a cAMP-mediated Decrease of in Vivo and in Vitro Growth and Invasiveness of Squamous Cell Carcinoma Cells¹

Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [H. M., A. M. G-G., R. L. D. C., D. E. B., T. G., A. J. P. K-S.], and Neuroscience Research Center of the Charité, Humboldt University, Faculty of Medicine, 10117 Berlin, Germany [K-H. B.]

Visinin-like protein-1 (VILIP-1) is a member of the neuronal EF-hand Ca²⁺-sensor protein family. VILIP-1 is expressed in the central nervous system where it plays a crucial role in regulating cAMP levels, cell signaling, and differentiation. Screening of mouse skin tumor cell lines for differentially expressed genes showed high-level VILIP-1 expression in less aggressive squamous cell carcinoma (SCC) and papilloma cell lines. Conversely, expression was markedly decreased or lost in invasive SCC and spindle cell carcinoma cell lines. In addition, immunohistochemistry of normal skin and primary tumors showed that VILIP-1 is expressed in basal cells of the normal intrafollicular epidermis as well as in basal cells of papillomas. The expression was decreased in low-grade SCCs and disappeared in most high-grade SCCs. When two high-grade carcinoma cell lines were transfected with VILIP1-cDNA, the VILIP-1 transfectants had significantly higher cAMP levels than the respective vector alone-transfected lines. VILIP-1-transfected cells were less invasive (both in vivo and in vitro) than the control transfectants. Reduced invasiveness and elevation of cAMP levels were accompanied by decreased MMP-9, as well as decreased RhoA activity. These results indicate that VILIP-1 plays an important role in regulating tumor cell invasiveness and that its loss could aid in enhancing the advanced malignant phenotype.

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