Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancer
Abstract Background Pancreatic 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...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2017-12-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-017-0655-5 |
| _version_ | 1818701310336172032 |
|---|---|
| author | Liang Zong Ke Chen Zhengdong Jiang Xin Chen Liankang Sun Jiguang Ma Cancan Zhou Qinhong Xu Wanxing Duan Liang Han Jianjun Lei Xuqi Li Qingyong Ma Zheng Wang |
| author_facet | Liang Zong Ke Chen Zhengdong Jiang Xin Chen Liankang Sun Jiguang Ma Cancan Zhou Qinhong Xu Wanxing Duan Liang Han Jianjun Lei Xuqi Li Qingyong Ma Zheng Wang |
| author_sort | Liang Zong |
| collection | DOAJ |
| description | Abstract Background Pancreatic 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. Methods Pancreatic 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. Results We 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. Conclusion Our 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. |
| first_indexed | 2024-12-17T15:18:48Z |
| format | Article |
| id | doaj.art-b24364895500424b998dd2da5b8810c0 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-17T15:18:48Z |
| publishDate | 2017-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-b24364895500424b998dd2da5b8810c02022-12-21T21:43:28ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662017-12-0136111210.1186/s13046-017-0655-5Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancerLiang Zong0Ke Chen1Zhengdong Jiang2Xin Chen3Liankang Sun4Jiguang Ma5Cancan Zhou6Qinhong Xu7Wanxing Duan8Liang Han9Jianjun Lei10Xuqi Li11Qingyong Ma12Zheng Wang13Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Anesthesiology, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of General Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong UniversityAbstract Background Pancreatic 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. Methods Pancreatic 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. Results We 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. Conclusion Our 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.http://link.springer.com/article/10.1186/s13046-017-0655-5Pancreatic cancerLipoxin A4Mesenchymal phenotypesTGF-β1Invasion and metastasis |
| spellingShingle | Liang Zong Ke Chen Zhengdong Jiang Xin Chen Liankang Sun Jiguang Ma Cancan Zhou Qinhong Xu Wanxing Duan Liang Han Jianjun Lei Xuqi Li Qingyong Ma Zheng Wang Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancer Journal of Experimental & Clinical Cancer Research Pancreatic cancer Lipoxin A4 Mesenchymal phenotypes TGF-β1 Invasion and metastasis |
| title | Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancer |
| title_full | Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancer |
| title_fullStr | Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancer |
| title_full_unstemmed | Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancer |
| title_short | Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancer |
| title_sort | lipoxin a4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine tgf β1 signaling in pancreatic cancer |
| topic | Pancreatic cancer Lipoxin A4 Mesenchymal phenotypes TGF-β1 Invasion and metastasis |
| url | http://link.springer.com/article/10.1186/s13046-017-0655-5 |
| work_keys_str_mv | AT liangzong lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT kechen lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT zhengdongjiang lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT xinchen lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT liankangsun lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT jiguangma lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT cancanzhou lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT qinhongxu lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT wanxingduan lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT lianghan lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT jianjunlei lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT xuqili lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT qingyongma lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer AT zhengwang lipoxina4reversesmesenchymalphenotypestoattenuateinvasionandmetastasisviatheinhibitionofautocrinetgfb1signalinginpancreaticcancer |