Rap1A promotes ovarian cancer metastasis via activation of ERK/p38 and notch signaling.

As one of the Ras-associated proteins, Rap1A has been linked to cancer initiation and development. However, the precise function of Rap1A in ovarian cancer is still not understood. Here, we show that Rap1A promotes ovarian cancer tumorigenesis and metastasis via stimulating cell proliferation, migration and invasion both in vivo and in vitro. Mechanistic study showed that Rap1A activates extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and Notch pathways, leading to the enhanced expression of several epithelial-mesenchymal transition (EMT) markers such as slug, zeb1, vimentin, fibronectin, and MMP9. However, the pretreatment of Rap1A-overexpressing cells with the Notch inhibitor DAPT or ERK inhibitor (U0126) inhibited the up-regulated expression of those molecules. These findings provide the first evidence linking Rap1A with ovarian cancer development through the ERK/p38 and Notch signaling pathways, indicating that Rap1A may be used as a novel diagnostic marker or a therapeutic target for ovarian cancer.