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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.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and accounts for more than 750,000 deaths/yr
Of note, increased LPAR3 in HCC was more pronounced than that observed for LPAR1 and occurred in 89% of patients (17/19), the most significant expression again being localized to the HCCNTL margin (Figure 1B)
In this study we report the microenvironment in human hepatocellular carcinoma (HCC) and non-tumor liver (NTL) is characterized by a subset of cells expressing LPAR1 and LPAR3, a profile shared by the human hepatic tumor-derived SKHep1 cell line
Summary
Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and accounts for more than 750,000 deaths/yr. Outcomes for HCC patients are often compromised by advanced tumor stage, impaired liver function as a result of underlying cirrhosis, and the presence of extra- and/ or intra-hepatic metastasis. The prognosis for HCC patients remains bleak, survival times of 7–12 months following diagnosis being typical [1, 2]. Lysophosphatidic acid (LPA) is a small phospholipid molecule comprising of a phosphate group, glycerol backbone, and single fatty acid chain. LPA exists in many structural variants based on degree of saturation, position of the C = C (when present), and number of carbons in the fatty acid chain [3, 4]. Following synthesis LPA regulates diverse cell functions across a range of cell types including proliferation, survival, and migration [3]. Based on www.impactjournals.com/oncotarget structural and phylogenetic homology LPARs can be divided into two major sub-groups: the endothelial differentiation gene (EDG) sub-family (LPARs 1–3), and the non-EDG sub-family (LPARs 4–6) [7]
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