1. ¹Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA
2. ²Department of Radiology, University of Virginia, Charlottesville, VA, USA
3. ³Department of Pathology, University of Virginia, Charlottesville, VA, USA
4. ⁴Department of Heath Evaluation Sciences, University of Virginia, Charlottesville, VA, USA

Correspondence: Dr D Theodorescu, Department of Molecular Physiology and Biological Physics, Box 800422, University of Virginia, Charlottesville, VA 22908, USA. E-mail: dt9d@virginia.edu

Received 26 April 2006; Revised 12 June 2006; Accepted 12 June 2006; Published online 31 July 2006.

Abstract

Most deaths from urinary bladder cancer are owing to metastatic disease. A reduction in Rho GDP Dissociation Inhibitor 2 (RhoGDI2) protein has been associated with increased risk of metastasis in patients with locally advanced bladder cancer, whereas in animal models, RhoGDI2 reconstitution in cells without expression results in lung metastasis suppression. Recently, we noted an inverse correlation between tumor RhoGDI2 and Neuromedin U (NMU) expression, suggesting that NMU might be a target of the lung metastasis suppressor effect of RhoGDI2. Here we evaluated whether NMU is regulated by RhoGDI2 and is functionally important in tumor progression. We used small interfering RNA knockdown of endogenous RhoGDI2 in poorly tumorigenic and non-metastatic human bladder cancer T24 cells and observed increased NMU RNA expression. Although NMU overexpression did not increase the monolayer growth of T24 or related T24T poorly metastatic human bladder cancer cells, it did augment anchorage-independent growth for the latter. Overexpression of NMU in T24 and T24T cells significantly promoted tumor formation of both cell lines in nude mice, but did not alter the growth rate of established tumors. Furthermore, NMU-overexpressing xenografts were associated with lower animal body weight than control tumors, indicating a possible role of NMU in cancer cachexia. NMU overexpression in T24T cells significantly enhanced their lung metastatic ability. Bioluminescent in vivo imaging revealed that lung metastases in T24T grew faster than the same tumors in the subcutaneous microenvironment. In conclusion, NMU is a RhoGDI2-regulated gene that appears important for tumorigenicity, lung metastasis and cancer cachexia, and thus a promising therapeutic target in cancer.