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

Janielle P. Maynard, Ju Seog Lee, Bo Hwa Sohn, Xiaoying Yu, Dolores Lopez-Terrada, Milton J. Finegold, John A. Goss, Sundararajah Thevananther

Research output: Contribution to journalArticle

9 Scopus citations

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 ATPmediated 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.

Original languageEnglish (US)
Pages (from-to)41162-41179
Number of pages18
JournalOncotarget
Volume6
Issue number38
DOIs
StatePublished - 2015
Externally publishedYes

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Keywords

  • Cell-cycle
  • Extracellular ATP
  • Hepatocellular carcinoma
  • JNK signaling
  • Purinergic receptors

ASJC Scopus subject areas

  • Oncology

Cite this

Maynard, J. P., Lee, J. S., Sohn, B. H., Yu, X., Lopez-Terrada, D., Finegold, M. J., Goss, J. A., & Thevananther, S. (2015). P2X3 purinergic receptor overexpression is associated with poor recurrence-free survival in hepatocellular carcinoma patients. Oncotarget, 6(38), 41162-41179. https://doi.org/10.18632/oncotarget.6240