RESUMEN
The peritoneal metastasis-associated phosphatase of regenerating liver-3 (PRL-3) is upregulated in gastric cancer. The phosphatidylinositol 3-kinase (PI3K)/RAC serine/threonine-protein kinase (AKT) signaling pathway acts downstream of PRL-3 in gastric cancer. However, the exact PRL-3 signaling mechanisms are poorly understood. The present study investigated whether PRL-3 facilitates the peritoneal metastasis of gastric cancer via the PI3K/AKT pathway in vivo and in vitro. Nude mouse models of peritoneal metastasis were established using SGC7901/PRL-3 cell lines. The results confirmed that the invasion and migration abilities of SGC7901/PRL-3 cells were significantly increased in these models. Furthermore, western blotting demonstrated that the expression of p-AKT, matrix metallopeptidase-2 (MMP-2) and -9 proteins increased in SGC7901/PRL-3 cells. These effects were suppressed in SGC7901 cell lines when PI3K was inhibited by LY294002. Furthermore, tumors derived from the peritoneal injection of SGC7901/PRL-3 cells were significantly smaller when the cells were grown in the presence of LY249002, compared with cells grown in its absence. These results indicated that targeted inhibition of the PI3K/AKT signaling pathway decreased the effects of PRL-3 on metastasis in vivo. Collectively, the results of the present study indicated that PRL-3 acts via the PI3K/AKT pathway to promote peritoneal metastasis and invasion of gastric cancer cells in vitro and in vivo.
RESUMEN
Peritoneal metastasis is the most frequent cause of death in patients with advanced gastric carcinoma (GC). The phosphatase of regenerating liver-3 (PRL-3) is recognized as an oncogene and plays an important role in GC peritoneal metastasis. However, the mechanism of how PRL-3 regulates GC invasion and metastasis is unknown. In the present study, we found that PRL-3 presented with high expression in GC with peritoneal metastasis, but phosphatase and tensin homologue (PTEN) was weakly expressed. The p-PTEN/PTEN ratio was also higher in GC with peritoneal metastasis than that in the normal gastric tissues. We also found the same phenomenon when comparing the gastric mucosa cell line with the GC cell lines. After constructing a wild-type and a mutant-type plasmid without enzyme activity and transfecting them into GC SGC7901 cells, we showed that only PRL-3 had enzyme activity to downregulate PTEN and cause PTEN phosphorylation. The results also showed that PRL-3 increased the expression levels of MMP-2/MMP-9 and promoted the migration and invasion of the SGC7901 cells. Knockdown of PRL-3 decreased the expression levels of MMP-2/MMP-9 significantly, which further inhibited the migration and invasion of the GC cells. PRL-3 also increased the expression ratio of p-Akt/Akt, which indicated that PRL-3 may mediate the PI3K/Akt pathway to promote GC metastasis. When we transfected the PTEN siRNA plasmid into the PRL-3 stable low expression GC cells, the expression of p-Akt, MMP-2 and MMP-9 was reversed. In conclusion, our results provide a bridge between PRL-3 and PTEN; PRL-3 decreased the expression of PTEN as well as increased the level of PTEN phosphorylation and inactivated it, consequently activating the PI3K/Akt signaling pathway, and upregulating MMP-2/MMP-9 expression to promote GC cell peritoneal metastasis.
