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

S. Y. Park, K. J. Jeong, N. Panupinthu, S. Yu, J. Lee, J. W. Han, J. M. Kim, J. S. Lee, J. Kang, C. G. Park, G. B. Mills, H. Y. Lee

Research output: Contribution to journalArticle

98 Scopus citations

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 C 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.

Original languageEnglish (US)
Pages (from-to)1351-1359
Number of pages9
JournalOncogene
Volume30
Issue number11
DOIs
StatePublished - Mar 17 2011
Externally publishedYes

Keywords

  • LPA1
  • human hepatocellular carcinoma cells
  • invasion
  • lysophosphatidic acid
  • matrix metalloproteinase-9

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Park, S. Y., Jeong, K. J., Panupinthu, N., Yu, S., Lee, J., Han, J. W., Kim, J. M., Lee, J. S., Kang, J., Park, C. G., Mills, G. B., & Lee, H. Y. (2011). Lysophosphatidic acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression. Oncogene, 30(11), 1351-1359. https://doi.org/10.1038/onc.2010.517