Prognostic role of KiSS-1 and possibility of therapeutic modality of metastin, the final peptide of the KiSS-1 gene, in urothelial carcinoma

Abstract

The KiSS-1 gene has been reported to be a metastasis suppressor gene in human melanoma. The gene 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 tumor metastasis 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 to determine their prognostic significance. Next, we examined the role of metastin 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 compared with lymph node metastasis. Metastin treatment significantly reduced the invasiveness of MBT-2V cells and inhibited the DNA-binding activity of NF-κB 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, n = 15) compared with controls (30.4 ± 5.1, n = 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-κB function.