Research Papers:

Expression and function of lysophosphatidic acid receptors (LPARs) 1 and 3 in human hepatic cancer progenitor cells

Valentina Zuckerman, Eugene Sokolov, Jacob H. Swet, William A. Ahrens, Victor Showlater, David A. Iannitti and Iain H. Mckillop _

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Oncotarget. 2016; 7:2951-2967. https://doi.org/10.18632/oncotarget.6696

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Valentina Zuckerman1,*, Eugene Sokolov1,*, Jacob H. Swet1, William A. Ahrens2, Victor Showlater1, David A. Iannitti1, Iain H. Mckillop1

1Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203

2Department of Pathology, Carolinas Medical Center, Charlotte, NC, USA 28203

*These authors contributed equally to this work

Correspondence to:

Iain McKillop, e-mail: [email protected]

Keywords: lysophosphatidic acid (LPA), hepatocellular carcinoma (HCC), SKHep1, cell migration, Gi-protein

Received: July 31, 2015     Accepted: November 16, 2015     Published: December 20, 2015


Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and is characterized by rapid tumor expansion and metastasis. Lysophosphatidic acid (LPA) signaling, via LPA receptors 1–6 (LPARs1–6), regulates diverse cell functions including motility, migration, and proliferation, yet the role of LPARs in hepatic tumor pathology is poorly understood. We sought to determine the expression and function of endothelial differentiation gene (EDG) LPARs (LPAR1–3) in human HCC and complimentary in vitro models. Human HCC were characterized by significantly elevated LPAR1/LPAR3 expression in the microenvironment between the tumor and non-tumor liver (NTL), a finding mirrored in human SKHep1 cells. Analysis of human tissue and human hepatic tumor cells in vitro revealed cells that express LPAR3 (HCC-NTL margin in vivo and SKHep1 in vitro) also express cancer stem cell markers in the absence of hepatocyte markers. Treatment of SKHep1 cells with exogenous LPA led to significantly increased cell motility but not proliferation. Using pharmacological agents and cells transfected to knock-down LPAR1 or LPAR3 demonstrated LPA-dependent cell migration occurs via an LPAR3-Gi-ERK-pathway independent of LPAR1. These data suggest cells that stain positive for both LPAR3 and cancer stem cell markers are distinct from the tumor mass per se, and may mediate tumor invasiveness/expansion via LPA-LPAR3 signaling.

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