Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-\u03b21 signaling in pancreatic cancer

Liang Zong,Jianjun Lei,Jiguang Ma,Qinhong Xu,Liang Han,Xuqi Li,Liankang Sun,Zhengdong Jiang,Cancan Zhou,Qingyong Ma,Ke Chen,Zheng Wang,Xin Chen,Wanxing Duan

doi:10.1186/s13046-017-0655-5

Abstract

BackgroundPancreatic cancer is a lethal disease in part because of its potential for aggressive invasion and metastasis. Lipoxin A4 (LXA4) is one of the metabolites that is derived from arachidonic acid and that is catalyzed by 15-lipoxygenase (15-LOX), and it has recently been reported to exhibit anti-cancer effects. However, the role of LXA4 in pancreatic cancer remains to be elucidated.MethodsPancreatic cell lines were treated with vehicle or LXA4, and the invasive capacity was then assessed by Transwell assays. The expression of epithelial and mesenchymal markers was determined by western blotting and immunofluorescence. Anti-TGF-β1 neutralizing antibody and exogenous recombinant human TGF-β1 (rhTGF-β1) were used to study the effect of LXA4 on the TGF-β signaling. A liver metastasis model was applied to investigate the effect of LXA4 in vivo. The correlation between the Lipoxin effect score (LES) and the clinical-pathological features of pancreatic cancer was also analyzed.ResultsWe found that in patients with pancreatic cancer, low LES was correlated with aggressive metastatic potential. The LXA4 activity, which was mediated by the LXA4 receptor FPRL1, could significantly suppress invasion capacity and mesenchymal phenotypes. The expression and autocrine signaling pathway activity of TGF-β1 were also downregulated by LXA4. In the liver metastasis model in nude mice, the stable analog of LXA4, BML-111, could inhibit the metastasis of pancreatic cancer cells.ConclusionOur results demonstrated that LXA4 could reverse mesenchymal phenotypes, which attenuated invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancer, which may provide a new strategy to prevent the metastasis of pancreatic cancer.

Highlights

Pancreatic cancer is a lethal disease in part because of its potential for aggressive invasion and metastasis
Lipoxin A4 (LXA4) inhibits the migration and invasion of pancreatic cancer cells To confirm the inhibitory functions of LXA4 on cell migration and invasion, Panc-1 and MIA PaCa-2 cell lines were treated with either vehicle or LXA4 (400 nM) for 24 h
We found that Transforming growth factor-β1 (TGF-β1) was down-regulated by LXA4, but when we knocked down formyl peptide receptor like-1 (FPRL1) by siRNA, LXA4 no longer exerted an effect on TGF-β1

Summary

Introduction

Pancreatic cancer is a lethal disease in part because of its potential for aggressive invasion and metastasis. The role of LXA4 in pancreatic cancer remains to be elucidated. Pancreatic cancer is a lethal malignancy that is characterized by aggressive invasion and metastasis [1]. Several mechanisms have been reported to regulate the invasion and metastasis of pancreatic cancer, including epithelial-mesenchymal transition (EMT). EMT is a metastasis-promoting process in which cancer cells lose epithelial phenotypes such as. Cancer cells with mesenchymal phenotypes exhibit plasticity, which facilitates the deformation, migration and, metastasis. Our previous studies have suggested that the induction of EMT significantly promoted cell invasion in both pancreatic cancer [3] and hepatocellular carcinoma [4]

Methods

Results

Discussion

Conclusion