Abstract
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.
Highlights
Ovarian carcinoma is the most lethal gynecological malignancy, which ranks the fifth leading cause of cancer death among women by 2016 [1]
A colony formation assay showed that the number of colonies formed by HEYA8- Rap1A cDNA was significantly increased (Fig. 1G), while the colony number formed by HEY- Rap1A sh1, or SKOV3-Rap1A sh2 cells were obviously decreased compared with those formed by controls (Fig. 1H, I)
Our findings revealed that Rap1A overexpression enhances ovarian cancer cell metastasis and tumorigenesis, which is similar to those reported in several other cancer types [11, 12, 23]
Summary
Ovarian carcinoma is the most lethal gynecological malignancy, which ranks the fifth leading cause of cancer death among women by 2016 [1]. It becomes an urgent demand to identify novel biomarkers for precise diagnosis, efficient treatment, and predictive prognosis of ovarian cancer patients. After two decades of study, it is believed that Rap1A plays a vital role in regulation of extracellular signal regulated kinase (ERK) activation and integrin-m ediated cellular activities, and is closely related to cell proliferation, adhesion, cell metastasis as well as osteoblast differentiation [5, 8,9,10]. Knocking down of Rap1A with miRNAs inhibited the Rac1/PAK1 pathway and attenuated prostate cancer cell proliferation, adhesion, and invasion [12, 13]. These results suggest that Rap1A may exert its effect as an oncogene. We investigated the role of Rap1A in some ovarian cancer cell lines and tried to uncover the Rap1A associated mechanism in ovarian cancer
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