P2X3 purinergic receptor overexpression is associated with poor recurrence-free survival in hepatocellular carcinoma patients

Abstract

P2 purinergic receptors are overexpressed in certain cancer tissues, but the pathophysiologic relevance of purinergic signaling in hepatocellular carcinoma (HCC) remains unknown. To examine the role of P2 purinergic signaling in the pathogenesis of HCC and characterize extracellular nucleotide effects on HCC cell proliferation, two independent HCC patient cohorts were analyzed for P2 purinergic receptor expression, and nucleotide treated HCC cell lines were evaluated for effects on proliferation and cell cycle progression. Our studies suggest that multiple P2 purinergic receptor isoforms are overexpressed in liver tumors, as compared to uninvolved liver, and dysregulation of P2 purinergic receptor expression is apparent in HCC cell lines, as compared to human primary hepatocytes. High P2X3 purinergic receptor expression is associated with poor recurrence-free survival (RFS), while high P2Y13 expression is associated with improved RFS. Extracellular nucleotide treatment alone is sufficient to induce cell cycle progression, via activation of JNK signaling, and extracellular ATP-mediated activation of P2X3 receptors promotes proliferation in HCC cells. Conclusion: Our analysis of HCC patient livers and HCC cells in vitro identifies a novel role for dysregulation of P2 purinergic signaling in the induction of hyper-proliferative HCC phenotype and identifies P2X3 purinergic receptors as potential new targets for therapy.

Inhibitory Effects of ATP and Adenosine on Cholangiocarcinoma Cell Proliferation and Motility

“…Therefore, it might not be the best candidate receptor for the inhibitory effects observed in this study. Although P2X3 receptor was also a common receptor among CCA cell lines and MMNK-1, it was recently reported to induce cell proliferation in hepatocellular carcinoma cell lines and to be associated with poor recurrence-free survival in patients (36). On the other hand, P2Y6, P2Y13, and P2X7 are the receptors that are expressed in CCA cells, but not in immortalized cholangiocarcinoma cells (MMNK-1).…”

Extracellular purines, purinergic receptors and tumor growth

“…P2X3R overexpression has been shown to promote proliferation via the JNK pathway in hepatocellular carcinoma and to be associated with an unfavorable prognosis. 133 The role of P2X3R in proliferation is intriguing as this receptor is rapidly desensitizing in the presence of physiological ATP concentrations, thus it seems that either in tumor cells its desensitization is defective or the TME contains factors that prevent its desensitization. The P2X5R is heavily expressed in human basal cell and squamous carcinomas, and is associated with differentiation, suggesting that its activation might indeed counteract cancer cell growth.…”

Targeting calcium signaling in cancer therapy

“…Numerous studies have demonstrated that P2 receptors involve in cancer cells and are expressed to a very high level in some cases, such as P2X3, P2X5, P2X7 and P2Y2 and P2Y442, 80, 81, 82, 83 (Table 1). In terms of clinical evaluation, P2X3 receptor overexpression was reported to be associated with poor recurrence-free survival in hepatocellular carcinoma patients 84 .…”