Gastric cancer is a growing concern due to its high prevalence worldwide and the increasing numbers of deaths related to the disease (1). While the etiology of gastric cancer carcinogenesis is thought to be multifactorial, molecular and genome-wide approaches have identified various genetic alterations associated with gastric tumorigenesis and progression (2). Two types of gastric cancers have been identified based on histological differences, epidemiology, etiology, pathogenesis and biological behavior. First is the diffuse type, which is characterized by infiltrating cells, poor differentiation, and noncohesive cancer cells with vast fibrous stroma, and the second is the intestinal type, which mostly features cohesive, and glandular-like cells (3). Among these, the diffuse type is more prevalent among younger individuals and metastasis of this type of gastric cancer is often identified in the peritoneum or lymph nodes, which makes prognosis extremely difficult. Currently, diffuse gastric cancer is treated with chemotherapy and targeted therapy using molecular approaches.
G protein-coupled receptors (GPCRs), which form the largest family of cell surface receptors, have been shown to modulate most physiological functions in the body. However, their roles in cancer development are not clearly understood (4, 5). Recently, P2RY1, a member of GPCRs has emerged as a cancer target because of its critical role in tumor growth and metastasis. P2RY1 activation via the endogenous agonist, ADP, was shown to alter multiple physiological functions (6–8). Interestingly, the P2RY1 receptor was shown to regulate cell growth and death in the following cancer cell lines; 1321N1 astrocytoma cells (9, 10), A375 melanoma cells (11, 12) and PC3 prostate cancer cells(13). Particularly, blocking the P2RY1 receptor using the antagonist MRS2179, reversed cell proliferation, suggesting that the P2RY1 receptor may have an anti-proliferative effect (11, 12). Additionally, other P2RY receptor subtypes, such as the Gq-coupled P2RY2, P2RY6, and P2RY11 receptors and the Gi-coupled P2RY12 and P2RY13 receptors have also been reported (14–17) to regulate cell death and growth (10, 14, 15, 18–20). Studies have shown that in aggressive gastric cancer tissues the levels of P2RY1 mRNA were low when compared to noncancerous gastric tissues. This indicates that the lack of P2RY1 may contribute to the development of aggressive gastric cancer growth. However, studies on the role of P2RY1 receptor signaling in gastric cancer are lacking. Although most cancers have been linked to specific DNA methylation, the epigenetic factors have not been associated with diffuse gastric cancer.
In this study, we used DNA methylation chip technology and previously published data to analyze the role of the P2RY1 receptor in gastric cancer. Our results showed that gastric cancer tissues have high levels of DNA methylation and low levels of the P2RY1 receptor protein expression when compared to noncancerous gastric tissues. Then, we used gastric cancer cells to analyze the involvement of P2RY1 receptor in cell death and growth. Subsequent activation of P2RY1 receptor using a selective P2RY1 receptor agonist, the ADP analogue MRS2365 (21) revealed that it induced apoptosis and inhibited cell proliferation. These results indicate that the P2RY1 receptor may be a potential target for the treatment of gastric cancer.