Therapeutic Discovery Prognostic Role of KiSS-1 and Possibility of Therapeutic Modality of Metastin, the Final Peptide of the KiSS-1Gene, in Urothelial Carcinoma

TheKiSS-1 gene has been reported to be ametastasis suppressor gene in humanmelanoma. Thegene product was isolated from human placenta as the ligand of GPR54, a G protein–coupled receptor, and the C-terminally amidated peptide of 54 amino acids is called metastin. The binding of metastin to GPR54 has been shown to inhibit tumormetastasis in some tumor cells; however, its function remains unclear in urothelial carcinoma.We first evaluated KiSS-1 expression and GPR54 expression in 151 patients with upper urinary tract urothelial carcinoma todetermine theirprognostic significance.Next,weexamined the roleofmetastin in the invasiveness and lung metastasis of MBT-2 variant (MBT-2V), which is a highly metastatic murine bladder cancer cell. Multivariate analysis revealed that KiSS-1 expression was an independent predictor of metastasis and overall survival. However, GPR54 expression was not selected. Hematogeneous metastasis had a significantly lower level of KiSS-1 expression comparedwith lymph nodemetastasis. Metastin treatment significantly reduced the invasiveness of MBT-2V cells and inhibited the DNA-binding activity of NF-kB by blocking its nuclear translocation, leading to a reduction in the expression and activity of matrix metalloproteinase-9. Metastin treatment dramatically prevented the occurrence of lung metastatic nodules (6.3 2.3, n1⁄4 15) compared with controls (30.4 5.1, n 1⁄4 15; P < 0.01), as well as had survival benefit. KiSS-1 plays an important role in the prognosis of upper tract urothelial carcinoma and metastin may be an effective inhibitor of metastasis in urothelial carcinoma through its blockade of NF-kB function. Mol Cancer Ther; 11(4); 853–63. 2012 AACR.