Higher LPA2 and LPA6 mRNA Levels in Hepatocellular Carcinoma Are Associated with Poorer Differentiation, Microvascular Invasion and Earlier Recurrence with Higher Serum Autotaxin Levels.

Kenichiro Enooku,Hiroki Kudo,Norihiro Kokudo,Yutaka Yatomi,Kazuhiko Koike,Masaya Sato,Makoto Kurano,Baasanjav Uranbileg,Harufumi Maki,Kiyoshi Hasegawa,Hitoshi Ikeda,William B Coleman

doi:10.1371/journal.pone.0161825

Kenichiro Enooku, Hiroki Kudo + Show 10 more

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https://doi.org/10.1371/journal.pone.0161825

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Journal: PloS one	Publication Date: Sep 1, 2016
Citations: 33	License type: CC BY 4.0

Affiliation: University of Tokyo Hospital, The University of Tokyo

Abstract

Hepatocellular carcinoma (HCC) commonly develops in patients with liver fibrosis; in these patients, the blood levels of lysophosphatidic acid (LPA) and its generating enzyme autotaxin (ATX) increase with the liver fibrosis stage. We aimed to examine the potential relevance of ATX and LPA in HCC. Fifty-eight HCC patients who underwent surgical treatment were consecutively enrolled in the study. Among the LPA receptors in HCC, higher LPA2 mRNA levels correlated with poorer differentiation, and higher LPA6 mRNA levels correlated with microvascular invasion, which suggested a higher malignant potential of HCC with increased LPA2 and LPA6 expression. In patients with primary HCC, neither LPA2 nor LPA6 mRNA levels were associated with recurrence. However, when serum ATX levels were combined for analysis as a surrogate for plasma LPA levels, the cumulative intra-hepatic recurrence rate was higher in patients in whom both serum ATX levels and LPA2 or LPA6 mRNA levels were higher than the median. However, the mRNA level of phosphatidic acid-selective phospholipase A1ɑ, another LPA-generating enzyme, in HCC patients was not associated with pathological findings or recurrence, even in combination with the expression of LPA receptors. Higher LPA2 mRNA levels were associated with poorer differentiation, and higher LPA6 levels were associated with microvascular invasion in HCC; both became a risk factor for recurrence after surgical treatment when combined with increased serum ATX levels. ATX and LPA receptors merit consideration as therapeutic targets of HCC.

Highlights

Lysophosphatidic acid (1- or 2-acyl-lysophosphatidic acid; LPA) is known as a circulatory lipid mediator and elicits a wide variety of biological responses, including cell migration, angiogenesis, and smooth muscle contraction [1, 2]
Through in vivo experiments that sought to clarify the potential roles of ATX and LPA in liver fibrosis, we found that serum ATX and plasma LPA levels increase with the stage of liver fibrosis in patients with chronic hepatitis C [13, 14] and in those with surgically treated hepatocellular carcinoma (HCC) [15]
Revealed a correlation between higher LPA2 mRNA levels and poorer differentiation and a correlation between higher LPA6 mRNA levels and microvascular invasion, which suggested that HCC with increased LPA2 and LPA6 expression may be associated with a high potential for malignancy

Summary

Introduction

Lysophosphatidic acid (1- or 2-acyl-lysophosphatidic acid; LPA) is known as a circulatory lipid mediator and elicits a wide variety of biological responses, including cell migration, angiogenesis, and smooth muscle contraction [1, 2]. Homozygous ATX-null was embryonically lethal in mice [7], suggesting the important role of the ATX-LPA axis in vivo. We have previously explored the potential roles of the ATX-LPA axis in the liver. We first found that LPA stimulates the proliferation of hepatic stellate cells [9], a key player in liver fibrosis. Through in vivo experiments that sought to clarify the potential roles of ATX and LPA in liver fibrosis, we found that serum ATX and plasma LPA levels increase with the stage of liver fibrosis in patients with chronic hepatitis C [13, 14] and in those with surgically treated hepatocellular carcinoma (HCC) [15]. A strong correlation between liver fibrosis and serum ATX levels or plasma LPA levels was confirmed in experimental animals, i.e., in rats with liver fibrosis induced by carbon tetrachloride [16]

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