ABSTRACT
Ras protein activator like 2 (RASAL2) has a cancer-related function, but plays inconsistent roles in different malignancies. This project was designed to determine the role of RASAL2 in carcinogenesis in gastric cancer. The Cancer Genome Atlas data revealed high levels of RASAL2 in gastric cancer tissue, which was confirmed in clinical specimens of gastric cancer via real-time quantitative PCR and western blotting assays. High RASAL2 was correlated with a reduced survival rate in gastric cancer patients. In gastric cancer cell lines, the silencing of RASAL2 restrained cellular proliferation, invasion and epithelial-to-mesenchymal transition, while enhancing chemosensitivity to cisplatin. Mechanistically, the silencing of RASAL2 was found to inhibit the activation of Yes-associated protein 1 (YAP1), a pro-oncogenic protein in gastric cancer, and decrease the expression of YAP1 target genes. The re-expression of constitutively active YAP1 substantially reversed RASAL2-silencing-produced antitumor effects. Moreover, treatment with YAP1 inhibitors could diminish RASAL2-overexpression-evoked oncogenic effects in gastric cancer cells. Additionally, gastric cancer cells with RASAL2 silencing exhibited a reduced ability to form xenograft tumors in nude mice. Collectively, our data demonstrate that the silencing of RASAL2 has noteworthy antitumor effects in gastric cancer cells via the suppression of YAP1 activation. This project underscores a vital role of the RASAL2/YAP1 axis in gastric progression and indicates that targeting this oncogenic axis may be applied as a potential therapeutic option for gastric cancer.
Subject(s)
Stomach Neoplasms , Animals , Cell Line, Tumor , GTPase-Activating Proteins , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Nude , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , YAP-Signaling Proteins , ras ProteinsABSTRACT
BACKGROUND: Pancreatic cancer is generally characterized with high levels of malignancy and poor prognosis. In addition, there are currently no effective therapeutic agents against the disease. However, apatinib which is a small molecular agent targeting the vascular endothelial growth factor receptor 2 (VEGFR-2), has been shown to generate favorable outcomes in gastric cancer. Therefore, the present study explored the effects of apatinib on pancreatic cancer. METHODS: The activity of the ASPC-1 or PANC-1 cells was examined through colony formation assays, wound healing experiments as well as the Transwell and Western blot (WB) analyses. Additionally, a xenograft model was established by subcutaneously injecting the ASPC-1 cells into nude mice. Microvessel density (MVD) and Ki-67 expression were examined through immunohistochemistry (IHC) and WB analyses. RESULTS: The findings showed that treatment with either 10 or 20 µM of apatinib led to a decrease in the proliferation, migration and invasion of ASPC-1 and PANC-1 cells. Additionally, apatinib significantly hindered xenograft growth. Moreover, there was a decrease in Ki-67 expression and MVD, 21 days after treatment with apatinib. The results also showed that apatinib had no effect on the levels of the VEGFR-2, ERK1/2 and AKT proteins although there was a significant decrease in the expression of phosphate VEGFR2 (p-VEGFR2), phosphate AKT (p-AKT) and phosphate ERK1/2 (p-ERK1/2). CONCLUSIONS: Apatinib inhibits the proliferation and migration of pancreatic cancer cells, blocking growth and angiogenesis in transplanted tumors. In addition, the underlying mechanism may involve phosphorylation of the PI3K/AKT and ERK1/2/MAPKs signaling pathways.
