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15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPARγ-mediated activation of p21WAF1/Cip1

Oncogene volume 33, pages 1101–1112 (2014)Cite this article

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A Corrigendum to this article was published on 09 October 2014

Abstract

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in prostaglandin (PG) metabolism. This study provides important evidence for inhibition of hepatocellular carcinoma (HCC) growth by 15-PGDH through the 15-keto-prostaglandin E2 (15-keto-PGE2)/peroxisome proliferator-activated receptor-γ (PPARγ)/p21WAF1/Cip1 signaling pathway. Forced overexpression of 15-PGDH inhibited HCC cell growth in vitro, whereas knockdown of 15-PGDH enhanced tumor growth parameters. In a tumor xenograft model in severe combined immunodeficiency mice, inoculation of human HCC cells (Huh7) with overexpression of 15-PGDH led to significant inhibition of tumor growth, whereas knockdown of 15-PGDH enhanced tumor growth. In a separate tumor xenograft model in which mouse HCC cells (Hepa1-6) were inoculated into syngeneic C57BL/6 mice, intratumoral injection of adenovirus vector expressing 15-PGDH (pAd-15-PGDH) significantly inhibited xenograft tumor growth. The antitumor effect of 15-PGDH is mediated through its enzymatic product, 15-keto-PGE2, which serves as an endogenous PPARγ ligand. Activation of PPARγ by 15-PGDH-derived 15-keto-PGE2 enhanced the association of PPARγ with the p21WAF1/Cip1 promoter and increased p21 expression and association with cyclin-dependent kinase 2 (CDK2), CDK4 and proliferating cell nuclear antigen. Depletion of p21 by short hairpin RNA reversed 15-PGDH-induced inhibition of HCC cell growth; overexpression of p21 prevented 15-PGDH knockdown-induced tumor cell growth. These results show a key 15-PGDH/15-keto-PGE2-mediated activation of PPARγ and p21WAF1/Cip1 signaling cascade that regulates hepatocarcinogenesis and tumor progression.

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Abbreviations

15-PGDH:

15-hydroxyprostaglandin dehydrogenase

15-keto-PGE2:

15-keto-prostaglandin E2

CDK:

cyclin-dependent kinase

COX-2:

cyclooxygenase-2

HCC:

hepatocellular carcinoma

IP:

immunoprecipitation

PCNA:

proliferating cell nuclear antigen

PGE2:

prostaglandin E2

PGR:

15-oxoprostaglandin-Δ13-reductase

PPARγ:

peroxisome proliferator-activated receptor-γ

PPRE:

peroxisome proliferator response element

SCID:

severe combined immunodeficiency

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Acknowledgements

We thank Dr Hsin-Hsiung Tai at the University of Kentucky for providing the 15-PGDH-adenoviral vector. This work was supported by National Institutes of Health grants CA102325, CA106280, CA134568 and DK077776.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA

    D Lu, C Han & T Wu

  2. Tongji University School of Life Science and Technology, Shanghai, China

    D Lu

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Correspondence to T Wu.

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Lu, D., Han, C. & Wu, T. 15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPARγ-mediated activation of p21WAF1/Cip1. Oncogene 33, 1101–1112 (2014). https://doi.org/10.1038/onc.2013.69

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