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. 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.
Highlights
Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide [1]
Our results reveal that 31% of patients in the TMC cohort exhibited ‘high’ expression of at least one P2 purinergic receptor isoform, while 60% of patients exhibited ‘high’ P2X3 mRNA expression in liver tumors, compared to their uninvolved areas (Figure 1A)
Further validation was done by immunohistochemical analysis of tumors, uninvolved areas of HCC patient livers, and normal liver which revealed that P2X3 protein overexpression was predominant in hepatocytes (Figure 1C)
Summary
Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide [1]. Frequency (%) of HCC patients with high mRNA expression of P2 Purinergic receptor subtypes as compared the uninvolved liver or normal liver. Studies suggest that extracellular ATP-mediated activation of P2Y2 receptor promotes proliferation and migration in HCC cells[17]; the role of the remaining 14 P2 receptor isoforms in HCC is currently unknown. ATP levels in the tumor interstitium of mice was measured in the hundreds micro molar range compared to near undetectable levels in healthy tissues [18]. Ectonucleotidases such as CD39 decrease extracellular nucleotide concentrations by hydrolyzing nucleotides to nucleosides and adenosine [19, 20]. P2 purinergic receptor expression and its role in hepatocyte cell cycle progression in human HCC remain unexplored
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