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Lysophosphatidic acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression

Oncogene volume 30, pages 1351–1359 (2011)Cite this article

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Abstract

Lysophosphatidic acid (LPA), produced extracellularly by autotaxin (ATX), has diverse biological activities implicated in tumor initiation and progression, including increasing cell survival, angiogenesis, invasion and metastasis. ATX, LPA and the matrix metalloproteinase (MMP)-9 have all been implicated in hepatocellular carcinoma (HCC) invasion and metastasis. We, thus sought to determine whether ATX with subsequent LPA production and action, including induction of MMP-9 could provide a unifying mechanism. ATX transcripts and LPA receptor type 1 (LPA1) protein are elevated in HCC compared with normal tissues. Silencing or pharmacological inhibition of LPA1 significantly attenuated LPA-induced MMP-9 expression and HCC cell invasion. Further, reducing MMP-9 activity or expression significantly inhibits LPA-induced HCC cell invasion, demonstrating that MMP-9 is downstream of LPA1. Inhibition of phosphoinositide-3 kinase (PI3K) signaling or dominant-negative mutants of protein kinase Cδ and p38 mitogen-activated protein kinase (MAPK) abrogated LPA-induced MMP-9 expression and subsequent invasion. We thus demonstrate a mechanistic cascade of ATX-producing LPA with LPA activating LPA1 and inducing MMP-9 through coordinate activation of the PI3K and the p38 MPAK signaling cascades, providing novel biomarkers and potential therapeutic targets for HCC.

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Acknowledgements

This work is supported by the Korea Science and the Engineering Fund through the Cancer Metastasis Research Center at Yonsei University (HYL), by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0022216, HYL) and by the Korean Institute of Environmental Science and Technology and the Korea Science & Engineering Foundation through the Infection Signaling Network Research Center (R13-2007-020-01000-0) at Chungnam National University (JMK). GBM and NP are supported by a grant from the Breast Cancer Research foundation and NCI RO1CA092160.

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  1. S Y Park and K J Jeong: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, Konyang University, Daejeon, Korea

    S Y Park, K J Jeong, J Kang, C G Park & H Y Lee

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

    N Panupinthu, S Yu, J-S Lee & G B Mills

  3. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Lee

  4. Department of Biochemistry and Molecular Biology, School of Pharmacy, Sungkyunkwan University, Suwon, Korea

    J W Han

  5. Cancer Research Institute, Regional Cancer Center and Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea

    J M Kim

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  1. S Y Park
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Correspondence to H Y Lee.

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Competing interests

GBM and NP receive sponsored research support from LPATH for the characterization of LPA inhibitors in ovarian cancer. The supported studies do not overlap with studies in this paper. GBM is on the scientific advisory and medical advisory boards of LPATH. The authors declare no conflict of interest.

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Park, S., Jeong, K., Panupinthu, N. et al. Lysophosphatidic acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression. Oncogene 30, 1351–1359 (2011). https://doi.org/10.1038/onc.2010.517

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