Journal
ACTA PHARMACOLOGICA SINICA
Volume 38, Issue 2, Pages 241-251Publisher
NATURE PUBL GROUP
DOI: 10.1038/aps.2016.122
Keywords
non-small cell lung cancer; metastasis; sulforaphane; microRNA; miR-616-5p; GSK3 beta; epithelial-mesenchymal transition (EMT)
Funding
- Fuzhou Science and Technology Plan Projects [2015S0096]
- Science and Technology Plan Projects of Fujian Province [2016D002]
- Health and Family Planning Commission Foundation of Fujian Province, China [2014-2-50, 2015-1-73]
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Sulforaphane is a common antioxidant selectively abundant in cruciferous plants, which exhibits effective anti-cancer actions in control of tumorigenesis or progression of various cancers. A recent study has shown that sulforaphane attenuates the EGFR signaling pathway in non-small cell lung cancer (NSCLC), suggesting its potential anti-metastatic effects. In this study we assessed the involvement of sulforaphane and miR-616-5p in epithelial-mesenchymal transition (EMT) and NSCLC metastasis. Sulforaphane suppressed the cell proliferation in human NSCLC cell lines H1299, 95C and 95D with IC50 values of 9.52 +/- 1.23, 9.04 +/- 1.90 and 17.35 +/- 2.03 mu mol/L, respectively. At low concentrations (1-5 mu mol/L), sulforaphane dose-dependently inhibited the migration and invasion of 95D and H1299 cells with relatively high metastatic potential. The anti-metastatic action of sulforaphane was confirmed in 95D and H1299 cell xenografts in vivo. In fresh NSCLC tissue samples from 179 patients, miR-616-5p levels were upregulated in late-stage NSCLCs, and strongly correlated with risk of NSCLC recurrence and metastasis. Consistent with the clinic observation, miR-616-5p levels in the 3 NSCLC cell lines were correlated with their metastatic ability, and were decreased by sulforaphane treatment. Silencing miR-616-5p markedly suppressed the migration and invasion of 95D cells in vitro and NSCLC metastasis in vivo. Further studies revealed that miR-616-5p directly targeted GSK3 beta and decreased its expression, whereas sulforaphane decreased miR-616-5p levels by histone modification, and followed by inactivation of the GSK3 beta/beta-catenin signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in NSCLC cells. Our findings suggest that sulforaphane is a potential adjuvant chemotherapeutic agent for the prevention of NSCLC recurrence and metastasis, and miR-616-5p can be clinically utilized as a biomarker or therapeutic target to inhibit metastasis.
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