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Originally published online as doi:10.2353/ajpath.2009.080207 on January 29, 2009

Published online before print January 29, 2009
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(American Journal of Pathology. 2009;174:1009-1016.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080207

Ribozyme-Mediated Targeting of I{kappa}B{gamma} Inhibits Melanoma Invasion and Metastasis

Sima Z. Torabian*, David de Semir*, Mehdi Nosrati*, Sepideh Bagheri*, Altaf A. Dar*, Sylvia Fong{dagger}, Yong Liu{dagger}, Scot Federman*, Jeff Simko{ddagger}, Chris Haqq§, Robert J. Debs{dagger} and Mohammed Kashani-Sabet*

From the Department of Dermatology,* the Auerback Melanoma Research Laboratory, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco; the California Pacific Medical Research Institute,{dagger} San Francisco; and the Departments of Pathology{ddagger} and Urology§ ; University of California San Francisco, San Francisco, California

I{kappa}B{gamma} is one member of a family of proteins that can inhibit the nuclear localization of nuclear factor-{kappa}B. However, the other specific functions of I{kappa}B{gamma} are still poorly understood, and its effects on tumor metastasis have not yet been characterized. We examined the consequences of targeting I{kappa}B{gamma} in melanoma cells using a hammerhead ribozyme. We developed stable transformant B16-F10 melanoma cell lines that express a ribozyme that targets mouse I{kappa}B{gamma} (I{kappa}B{gamma}-144-Rz). Tail-vein injection of B16-F10 cells that stably express I{kappa}B{gamma}-144-Rz into mice resulted in a significant reduction of the metastatic potential of these cells. I{kappa}B{gamma}-144-Rz-expressing B16 cells were shown to have increased transcriptional activity of nuclear factor-{kappa}B. We then showed that I{kappa}B{gamma}-144-Rz-expressing cells demonstrated both reduced invasion and increased apoptosis, suggesting the existence of pathways through which I{kappa}B{gamma} promotes melanoma metastasis. Using gene expression profiling, we identified a differentially expressed gene set that is regulated by the stable suppression of I{kappa}B{gamma} that may participate in mediating its anti-metastatic effects; we also confirmed the altered expression levels of several of these genes by quantitative real time polymerase chain reaction. Plasmid-mediated expression of I{kappa}B{gamma}-144-Rz produced a significant inhibition of the metastatic progression of B16-F10 cells to the lung and resulted in significant anti-invasive and pro-apoptotic effects on murine Lewis lung carcinoma cells. Our results suggest a novel role for I{kappa}B{gamma} in promoting the metastatic progression of melanoma.






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