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.