title: Expression and function of lysophosphatidic acid receptors (LPARs) 1 and 3 in human hepatic cancer progenitor cells.
abstract: 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.
authors.affiliation: Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203.
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuckerman
authors.affiliation: Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203.
authors.forename: Eugene
authors.initials: E
authors.lastname: Sokolov
authors.affiliation: Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203.
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Swet
authors.affiliation: Department of Pathology, Carolinas Medical Center, Charlotte, NC, USA 28203.
authors.forename: William A
authors.initials: WA
authors.lastname: Ahrens
authors.affiliation: Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203.
authors.forename: Victor
authors.initials: V
authors.lastname: Showlater
authors.affiliation: Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203.
authors.forename: David A
authors.initials: DA
authors.lastname: Iannitti
authors.affiliation: Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA 28203.
authors.forename: Iain H
authors.initials: IH
authors.lastname: Mckillop
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C000609549:LPAR1 protein, human; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid
keywords: Gi-protein; SKHep1; cell migration; hepatocellular carcinoma (HCC); lysophosphatidic acid (LPA)