PRL-3 promotes the peritoneal metastasis of gastric cancer through the PI3K/Akt signaling pathway by regulating PTEN

Abstract

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.

MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer (Review)

“…Function of the PTEN/PI3K/Akt pathway in GC. PI3K signaling is vital in regulating multiple fundamental cellular activities, including cell proliferation, apoptosis and metastasis (49). With frequent alterations identified in GC, the PTEN/PI3K/Akt pathway is significantly involved in gastric carcinogenesis and progression (11,50).…”

Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression

“…Further methods to externally increase MMP activity include mechanical induction to replicate a more rigid ECM[224], injection of MMP regulators[225], gene delivery[226], or oxidative stress[227]. Curiously, mechanical induction of MMP overexpression in MDA-MB-231 cells was correlated with advanced resistance to free drug chemotherapeutics, but was not tested against MMP-induced controlled release systems[224].…”

The Clinical Implication of PTEN and FAK Expression in Gastric Cancer Patients

“…It was reported that downregulation of PTEN was correlated with peritoneal recurrence in GC, 13,14 which was associated with the activation of the PI3K/AKT pathway. 13 In renal cell carcinoma, 15 patients with bone metastasis were reported to have lower PTEN expression than those without. Bone metastasis might be caused by AKT and integrin a5 signaling.…”

“…The conclusion might not be reliable, although the statistical value is considerable. However, few studies 13,14 investigated the correlation between PTEN expression and recurrence pattern in GC, and the patient number enrolled is limited; this study enrolled the largest population to date to investigate their relationship. The enrollment of more patients is required to verify our findings in the future.…”