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

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 dominantnegative mutants of protein kinase Cd and p38 mitogenactivated 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.

<i>In vitro</i> effect of lysophosphatidic acid on proliferation, invasion and migration of human ovarian cancer cells

“…However, LPA exerts a significant effect upon VEGF and VEGFR, indicate that blockage of CXCR4/CXCL12 biological axis can inhibit tumor growth and suppress the role of VEGF in vascularization, which is consistent with previous reports [13,14]. The findings in this investigation may provide alternative evidence for the clinical treatment of ovarian cancer.…”

The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion

“…Upon binding to series of cell-surface G-protein-coupled receptors, LPA activates MMP-2 (Fishman et al, 2001) and induces the expression of uPA (Pustilnik et al, 1999) to augment ovarian cancer invasion and metastasis. In addition, our recent data show that LPA aggravates human hepatocellular carcinoma invasion by secreting MMP-9 (Park et al, 2011a).…”

“…In vitro invasion and migration assay In vitro invasion assay was performed with invasion assay kit with Matrigel-coated inserts (BD Biosciences, San Jose, CA, USA) as described previously (Park et al, 2011a). Volume of 1 Â 10 5 cells/well was added to the upper compartment of the invasion chamber with or without pharmacological inhibitors.…”

Cholera toxin inhibits human hepatocarcinoma cell proliferation in vitro via suppressing ATX/LPA axis

“…Using an LPA 1 and LPA 3 specific antagonist [27] (Ki16425), LPA 1 -specific small interfering RNA (siLPA 1 ), LPA 2 -specific small interfering RNA (siLPA 2 ), and LPA 3 -specific small interfering RNA (siLPA 3 ) in proliferation assays, we conclude that the LPA 1 receptor plays the main role in the proliferation of HCC cells. Recently, Park et al also determined the involvement of LPA 1 receptor activation by LPA produced by ATX activity in HCC invasion and metastasis, which suggests these could be novel biomarkers and potential therapeutic targets for HCC [28] . Despite data demonstrating the association of ATX and LPA with invasion and metastasis of HCC, whether CT inhibits HCC proliferation by interfering with LPA production is unknown.…”