Expression of HGF/NK4 in ovarian cancer cells suppresses intraperitoneal dissemination and extends host survival

Peritoneal dissemination is the most frequent progression pathway of ovaria n cancer and is therefore a key step, to improve the prognosis. NK4, a larg e part of the a-chain of hepatocyte growth factor, is known to inhibit canc er cell migration. To characterize the function of NK4 and investigate its potential role in gene therapy of ovarian cancer, we introduced NK4 cDNA to an ovarian cancer cell line HRA and investigated its effects both in vitro and in vivo. HRA cells were transfected with either NK4 or luciferase-expr ession plasmids. After selection, NK4-expressing HRA cells (HRA/NK4) and th e control cells (HRA/LUC) were obtained. NK4 was detected in the culture su pernatant of HRA/NK4 by Western analysis. Migration capabilities of the cel ls were evaluated in vitro by scratch wound healing assay. The number of mi grated cells was significantly smaller in the HRA/NK4 cultures than that in the control cultures (HRA or HRA/LUC). Also, the, culture supernatant of H RA/NK4 significantly suppressed migration of control cells. This suppressiv e effect was observed when NK4-expressing cells were mixed with control cel ls at the ratio of 25% or more. in the in vivo experiments, HRA transfectan ts were injected intraperitoneally. The number of intraperitoneal tumors of HRA/NK4 was much smaller than that of control. In mice injected with HRA/N K4, ascites formation was suppressed and the survival was significantly pro longed. These findings suggest that NK4-mediated gene therapy can improve t he prognosis of ovarian cancer by suppressing peritoneal dissemination.