The Effect Of γ-secretases Inhibitor In The Carcinogenesis And Metastasis Of Gastric Cancer

Objective: Gastric Cancer(GC)is one of the most common malignant tumors in China. Invasion and metastasis are the most important features, and also the major cause of death related with GC. In this research, we study the effect of γ-secretases inhibitor(GSI)(LY411575 and LY900009) on the ability of gastric cancer cell lines carcinogenesis and metastasis in vitro and in vivo. Furthermore, this study provides theoretical foundations for early diagnosis and targeted therapies of GC.Methods:(1). We evaluated the proper concentration of γ-secretases inhibitor via CCK-8 method and draw the IC50 curve.(2).Use CCK-8 、plate clone formation assay and soft agar clone assay were adopted to detect the effect of γ-secretase inhibitor in gastric cancer cell in vitro.(3). The silent of PS-1was infected into MGC-803 cells to generate stable cell models(MGC-803/sh PS-1),the relative expression of PS-1 was detected by Western-blot to evaluate the effect of interference.(4). On the foundation of establishment of GC models which were inoculated with(MGC-803/sh PS-1) and its control cells in the back, we measured the cell proliferation and xerograft growth in vivo.(5). We investigated the effects of γ-secretase inhibitor on metastasis through inoculating MGC-803 into caudal vein of nude mice to establish another GC models. HE staining to confirm liver and lung metastasis.Results:(1). The available concentration of the γ- secretase inhibitors(LY411575,LY900009) on gastric cancer cell MGC-803 and EC50 HGC-27 were 0.093 ±0.005 and 0.924 ± 0.008 mg / L.(2). Compared with the negative control group, γ-secretase inhibitors could decrease the proliferative rate of gastric cancer cells, the difference was statistically significant(P <0.01).(3). γ- secretase inhibitors significantly inhibit the capacity of cell plates and soft agar cloning formation in gastric cancer, the difference were both statistically significant(P <0.01).(4). γ-secretase inhibitors can significantly constrain the invasion and lateral migration ability of gastric cancer cells(P <0.01).(5). Compared with the negative control group, the inhibitory γ- secretase activity also significantly reduces tumor size in nude mice, the difference was statistically significant(P <0.01).(6). Inhibiting γ-secretase activity could either degrade gastric cancer cells in nude mice lung and liver metastasis rate(P <0.05).Conclusions:(1).LY411575 and LY900009 could significantly inhibit γ- secretase activity.(2). γ- secretase inhibitors can impair gastric cancer cell MGC-803 and HGC-27 proliferation, invasion and migration both in vitro and in vivo.(3). Once silence of PS-1 expression, the γ- secretase activity would be suppressed, which lead to alter the tumorgenesis of gastric cancer cells in vivo.