Over the past 50 years, gastric cancer incidence and related mortality have decreased significantly worldwide. However, in Asia, gastric cancers still remain prevalent and result in loss of life in large numbers. This is largely due to poor prognosis, which results in metastasis and subsequent death (26). In this study, we found that the P2RY1 receptor may play a critical role in causing gastric cancer. Our results have shown that 4 higher methylated sites of P2RY1’s promoter region could be used as markers for the prognosis of gastric cancers.
In the diverse MAPK signaling pathway, expression of early genes such as c-Fos, c-Jun, and Elk1 is regulated by phosphorylation of the transcription factors (27, 28). Specifically, c-Fos and c-Jun phosphorylation has been shown to increase astrocyte proliferation and GFAP expression. Besides, in vitro and in vivo studies have shown that ATP can upregulate the expression of the c-Fos protein and the formation of AP-1 transcriptional complexes (29, 30). In the present study, we found that P2RY1 receptor activation in SGC7901 can induce apoptosis. This result is consistent with previous reports after the activation of the P2RY1 receptor (9–13). Previous studies have also shown that the P2RY1 receptor-mediated apoptosis in astrocytoma cells (1321N1) and prostate cancer cells (PC3) correlated with ERK1/2 activation. Our study further examined the potential involvement of MAPK signaling in gastric cancer cells. We showed that the selective activation of P2RY1 via its agonist, MRS2365, can induce ERK1/2 phosphorylation and subsequent ELK1/c-Fos/c-Jun phosphorylation, suggesting a crucial role of ERK1/2 signaling in gastric cancer cells (Fig. 5). The Ras-Raf-MEK-ERK pathway activation is known to be critical for the proliferation of many human tumors (31–33) thus this pathway may serve as an important molecular target for anticancer therapy (34, 35). Specifically, the P2RY1 receptor may serve as a novel anticancer target.
Besides inducing apoptosis, P2RY1 receptors are also known to inhibit cell proliferation. The anti-proliferative effect of P2RY1 receptors was first demonstrated in 1321N1 astrocytoma cells that expressed a recombinant human P2RY1 receptor(36). We also found that selective activation of P2RY1 receptors using the agonist, MRS2365, can inhibit SGC7901 cell proliferation, which is consistent with previous studies (11, 37).
In previous studies (38–41), the expression of the P2RY1 receptor is low in gastric cancer tissues. In this study, we also showed the beneficial effects of the P2RY1 agonist, which has been shown in other cancer models such as melanoma, where P2RY1 receptor was highly expressed (12). The enhanced in vivo stability of the di-nucleotide P2RY1 agonists (42) also increases their potential use to treat other diseases such as diabetes or thrombosis (43).
In summary, we have demonstrated that, in gastric cancer tissues, the P2RY1 gene is highly methylated, while P2RY1 mRNA are expressed at relatively low levels when compared to noncancerous tissue. We also showed that MRS2365, the selective agonist of the P2RY1 receptor, can induce ERK1/2 phosphorylation that may inhibit cell proliferation/migration and induce apoptosis. Together, these findings suggest that P2RY1 plays an important role in the development of gastric cancer. Finally, our results underscore the potential therapeutic application of P2RY1. The pro-apoptotic and anti-proliferative effects induced by P2RY1 receptor activation indicate that the P2RY1 receptor might be an attractive target for the treatment of gastric cancer.