PLXDC2 Enhances Invadopodium Formation to Promote Invasion and Metastasis of Gastric Cancer Cells via Iteracting with PTP1B

Abstract

Background: Plexin-domain containing 2 (PLXDC2) has been reported as an oncoprotein in several human malignancies. However, its expression and roles in gastric cancer remain largely unclear. Methods: The expression of PLXDC2 in 170 gastric cancer specimens was measured by using immunohistochemical staining and its clinical relevance was statistically analyzed. Matrigel-transwell invasion assays and mouse intraperitoneal metastasis models with PLXDC2-silencing and -overexpressing gastric cells were performed to explore the biological functions of PLXDC2 in gastric cancer cells. RNA-Seq, immunofluorescence and Co-IP analyses were used to investigate the potential molecular mechanisms of PLXDC2 action in gastric cancer. Results: PLXDC2 was highly expressed in gastric cancer tissues, and the expression levels were positively correlated with clinicopathological features, but negatively with the patients’ outcome. Cox regression analysis identified PLXDC2 as an independent prognostic indicator for the patients. Knockdown of PLXDC2 markedly suppressed the in vitro invasion and in vivo metastasis of gastric cancer cells, while overexpression of PLXDC2 resulted in opposite effects. Mechanistically, PLXDC2 inhibited dephosphorylation of phosphorylated Cortactin by physically interacting with PTP1B, an important tyrosine phosphatase, thereby promoting the formation of invadopodium. Conclusions: PLXDC2 contributes to the invasion and metastasis of gastric cancer by inhibiting PTP1B to facilitate the invadopodium formation, and may serve as a potential prognostic biomarker and a therapeutic target for this disease.