Autotaxin expression and its connection with the TNF-alpha-NF-κB axis in human hepatocellular carcinoma

Abstract

BackgroundAutotaxin (ATX) is an extracellular lysophospholipase D that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Both ATX and LPA have been shown to be involved in many cancers. However, the functional role of ATX and the regulation of ATX expression in human hepatocellular carcinoma (HCC) remain elusive.ResultsIn this study, ATX expression was evaluated in tissues from 38 human HCC and 10 normal control subjects. ATX was detected mainly in tumor cells within tissue sections and its over-expression in HCC was specifically correlated with inflammation and liver cirrhosis. In addition, ATX expression was examined in normal human hepatocytes and liver cancer cell lines. Hepatoma Hep3B and Huh7 cells displayed stronger ATX expression than hepatoblastoma HepG2 cells and normal hepatocytes did. Proinflammtory cytokine tumor necrosis factor alpha (TNF-α) promoted ATX expression and secretion selectively in Hep3B and Huh7 cells, which led to a corresponding increase in lysophospholipase-D activity. Moreover, we explored the mechanism governing the expression of ATX in hepatoma cells and established a critical role of nuclear factor-kappa B (NF-κB) in basal and TNF-α induced ATX expression. Further study showed that secreted enzymatically active ATX stimulated Hep3B cell invasion.ConclusionsThis report highlights for the first time the clinical and biological evidence for the involvement of ATX in human HCC. Our observation that links the TNF-α/NF-κB axis and the ATX-LPA signaling pathway suggests that ATX is likely playing an important role in inflammation related liver tumorigenesis.

TNF-α potentiates lysophosphatidic acid-induced COX-2 expression via PKD in human colonic myofibroblasts

“…This pathway implies that other molecules downstream of PKD may also be involved. In other cell types, including Swiss 3T3 fibroblasts, a prominent mechanism by which PKD mediates GPCR-induced signaling is by increasing the duration of MEK/ERK/90-kDa ribosomal S6 kinase activation (46), which is also one of the major pathways leading to COX-2 transcriptional activation (1,45,60). It is plausible that the ERKs play a role in relaying the downstream PKD signal.…”

“…LPA-induced protein kinase D (PKD) activation is augmented by prior cell treatment with TNF-␣. A: 18Co cells were incubated in the presence or absence of TNF-␣ (8 ng/ml) for 18 h, followed by stimulation with LPA (10 M) over various times (15,30,60,120, 240 min, as indicated). The cells were analyzed by Western blotting using an antibody that detects the COOH-terminal autophosphorylation site of PKD (Ser 910 in human PKD).…”

Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B

“…In recent years, substantial progress has been achieved in producing sufficient data on gene expression in HepG2 and Hep3B cell lines, by using several different assay techniques including PCR (Cheng et al 2003), Western Blotting (Gangneux et al 2003;Kusaba et al 2007;Wu et al 2010), immunoprecipitation (Bressac et al 1990), zymography , or electrophoretic mobility shift assay (EMSA) (Chiao et al 2002). Table 1 lists all those genes that have been found to express differently in HepG2 and Hep3B cell lines.…”

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

“…Compatible with the elevated ATX transcripts, increased LPA levels are present in the liver, bile and serum of patients with HCC compared with healthy individuals (Skill et al, 2009). In addition, recent data indicate that ATX can promote HCC cell invasion (Wu et al, 2010). As the activities of ATX appear to be due, primarily if not solely, to the production and action of LPA, the effect of LPA on HCC progression needs to be clarified.…”