Inhibition of lung cancer growth and metastasis by DHA and its metabolite, RvD1, through miR-138-5p/FOXC1 pathway

Background Non small cell lung cancer (NSCLC) is one of the most common cancers in the world. DHA is known to be capable of suppressing NSCLC cell proliferation and metastasis. However, the mechanisms by which DHA exhibits its antitumor effects are unknown. Here we aimed to identify the effects and...

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Published in:Journal of experimental & clinical cancer research 2019-11, Vol.38 (1), p.1-479, Article 479
Main Authors: Bai, Xiaoming, Shao, Jiaofang, Zhou, Sujin, Zhao, Zhenggang, Li, Fanghong, Xiang, Rong, Zhao, Allan Z, Pan, Jinshun
Format: Article
Language:English
Subjects:
Analysis
Biotechnology industries
Cancer metastasis
Cancer prevention
Cell growth
Fatty acids
FOXC1
Gene expression
Genetic engineering
Growth
Growth and invasion
Luciferase
Lung cancer
Medical prognosis
Medical research
Metabolites
Metastasis
MicroRNA
miR-138-5p
Non-small cell lung cancer
Novels
Omega 6 fatty acids
Penicillin
Plasmids
Polyunsaturated fatty acids
Resolvin D1
Small cell lung cancer
Surgery
Transgenic animals
Tumors
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Summary:Background Non small cell lung cancer (NSCLC) is one of the most common cancers in the world. DHA is known to be capable of suppressing NSCLC cell proliferation and metastasis. However, the mechanisms by which DHA exhibits its antitumor effects are unknown. Here we aimed to identify the effects and mechanisms of DHA and its metabolites on lung cancer cell growth and invasion. Methods As measures of cell proliferation and invasion ability, the cell viability and transwell assays were used in vitro. Transgenic mfat-1 mice, which convert [omega]-6 PUFAs to [omega]-3 PUFAs, were used to detect the effect of endogenous DHA on tumor transplantation. An LC - MS/MS analysis identified the elevation of several eicosanoid metabolites of DHA. By using qPCR miRNA microarray, online prediction software, luciferase reporter assays and Western blot analysis, we further elucidated the mechanisms. Results Addition of exogenous DHA inhibited the growth and invasion in NSCLC cells in vitro. Endogenously produced DHA attenuated LLC-derived tumor growth and metastasis in the transgenic mfat-1 mice. Among the elevation of DHA metabolites, resolvin D1 (RvD1) significantly contributed to the inhibition in cell growth and invasion. MiRNA microarray revealed that the level of miR-138-5p was significantly increased after RvD1 treatment. MiR-138-5p mimics decreased cell viability and invasion; while miR-138-5p inhibitor abolished RvD1-mediated suppression of cell viability and invasion. The expression of FOXC1 was significantly reduced upon overexpression of miR-138-5p while luciferase reporter assay showed that FOXC1 was a direct target of miR-138-5p. In vivo, endogenous DHA by the mfat-1 transgene enhanced miR-138-5p expression and decreased FOXC1 expression. Furthermore, overexpression of FOXC1 reversed the inhibition in cell viability and invasion induced by RvD1 treatment. Conclusions These data identified the RvD1/miR-138-5p/FOXC1 pathway as a novel mechanism by DHA and its metabolite, RvD1, and the potential of targeting such pathway as a therapeutic strategy in treating NSCLC. Keywords: Resolvin D1, miR-138-5p, FOXC1, Growth and invasion, Lung cancer
ISSN:1756-9966
0392-9078
1756-9966
DOI:10.1186/s13046-019-1478-3