Research Papers:

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 and Sundararajah Thevananther _

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Oncotarget. 2015; 6:41162-41179. https://doi.org/10.18632/oncotarget.6240

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Janielle P. Maynard1,2, Ju-Seog Lee3, Bo Hwa Sohn3, Xiaoying Yu4, Dolores Lopez-Terrada5, Milton J. Finegold2,5, John A. Goss2,6 and Sundararajah Thevananther1,2

1 Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children’s Liver Center, Houston, TX, USA

2 Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA

3 Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA

4 Department of Medicine, Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA

5 Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

6 Department of Surgery, Baylor College of Medicine, Houston, TX, USA

Correspondence to:

Sundararajah Thevananther, email:

Keywords: hepatocellular carcinoma, cell-cycle, extracellular ATP, purinergic receptors, JNK signaling

Received: June 02, 2015 Accepted: September 17, 2015 Published: October 26, 2015


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.

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