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Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer

Oncogene volume 33, pages 2846–2856 (2014)Cite this article

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Abstract

The Y-box binding protein-1 (YB-1) transcription factor is associated with unfavorable clinical outcomes. However, the mechanisms underlying this association remain to be fully elucidated. We demonstrate that YB-1 phosphorylation, indicative of YB-1 activation, is a powerful marker of outcomes for ovarian cancer patients. In ovarian cancer, YB-1 phosphorylation is induced by activation of the lysophosphatidic acid (LPA) receptor (LPAR) via SRC-dependent transactivation of the epidermal growth factor receptor (EGFR) that is coupled to MAPK/p90 ribosomal S6 kinase (p90RSK), but not phosphatidylinositol 3-kinase (PI3K)/AKT signaling. Activation of the LPAR/SRC/EGFR/MAPK/p90RSK/YB-1 axis leads to production of the EGFR ligand amphiregulin (AREG). AREG induces ongoing YB-1 phosphorylation as well as YB-1-dependent AREG expression, thus constituting an AREG/YB-1 self-reinforcing loop. Disruption of transactivation of the EGFR and the downstream self-reinforcing loop decreases invasiveness of ovarian cancer cells in vitro and limits ovarian cancer growth in xenograft models. These findings established the regulation and significance of YB-1 phosphorylation, therefore further exploration of this signaling axis as a therapeutic avenue in ovarian cancer is warranted.

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Abbreviations

AREG:

Amphiregulin

EGFR:

Epidermal growth factor receptor

GPCR:

G-protein-coupled receptor

HER:

human epidermal growth factor receptor

IGF-1:

insulin-like growth factor 1

IGF1R:

insulin-like growth factor 1 receptor

LPA:

lysophosphatidic acid

LPAR:

lysophosphatidic acid receptor

p90RSK:

p90 ribosomal S6 kinase

PI3K:

phosphatidylinositol 3-kinase

RPPA:

reverse phase protein array

TCGA:

The Cancer Genome Atlas

TGFα:

transforming growth factor-α

YB-1:

Y-box binding protein-1

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Acknowledgements

We thank Drs Meng Gao and Zhiyong Ding at MD Anderson Cancer Center for authenticating the AKT1/AKT2 knockout cell lines. This work was supported by NIH grants R01CA92160 and P01CA099031 (to G.B.M.), and R01CA098372 (to J.R.G.), the Breast Cancer Research Foundation (to G.B.M.), the National Research Foundation of Korea 2011-0015761 (to H.Y.L.), Canadian Institutes of Health Research (to S.E.D.), the SPORE in head-and-neck cancer P50CA197190 (to J.R.G.), the American Cancer Society (to J.R.G.) and CCSG core grant CA16672 (to MD Anderson Cancer Center).

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Authors and Affiliations

  1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    N Panupinthu, S Yu, D Zhang, F Zhang, Y Lu & G B Mills

  2. Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand

    N Panupinthu

  3. Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M Gagea

  4. Department of Otolaryngology and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

    J R Grandis

  5. Departments of Pediatrics and Experimental Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

    S E Dunn

  6. Department of Pharmacology, College of Medicine, Konyang University, Daejeon, Republic of Korea

    H Y Lee

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Panupinthu, N., Yu, S., Zhang, D. et al. Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer. Oncogene 33, 2846–2856 (2014). https://doi.org/10.1038/onc.2013.259

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