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Open AccessArticle

Dietary Flavonoids Luteolin and Quercetin Inhibit Migration and Invasion of Squamous Carcinoma through Reduction of Src/Stat3/S100A7 Signaling

1
Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan
2
Food and Drug Administration, Ministry of Health and Welfare, Taipei 11561, Taiwan
3
Department of Surgery, Wan-Fang Hospital, Taipei Medical University, Taipei 11034, Taiwan
4
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11034, Taiwan
5
Cancer Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11034, Taiwan
6
Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11034, Taiwan
7
Departments of Medicine and Pediatrics, Duke University Hospital, Durham, NC 27704, USA
8
Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan
9
Department of Nursing, Ching Kuo Institute of Management and Health, Keelung 20301, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Antioxidants 2019, 8(11), 557; https://doi.org/10.3390/antiox8110557
Received: 1 November 2019 / Revised: 13 November 2019 / Accepted: 13 November 2019 / Published: 15 November 2019
(This article belongs to the Special Issue Dietary Antioxidants in Cancer Chemoprevention)
Flavonoids are well-known antioxidants and have shown the ability to prevent tumor formation and recurrence. Especially in dietary flavonoids, they have provided convenience and consistence of intake for long-term prevention of tumor formation. Previous reports suggested that S100 calcium-binding protein A7 (S100A7) might activate epithelial–mesenchymal transition (EMT) signaling and promote the metastasis of tumor cells; however, the regulatory signaling was unclear. In this study, we found that S100A7 was highly expressed in cancer cells and could be reduced by luteolin (Lu) and quercetin (Qu) through Src/Stat3 signaling. We found that the protein levels of S100A7, phosphorylated Src (p-Src), and p-Stat3 were increased in A431-III cells. Flavonoids Lu and Qu reduce protein levels of p-Src, p-Stat3 and S100A7 in A431-III cells. Treatment of A431-III cells with Src inhibitor SU6656 and Stat3 inhibitor S3I-201 also reduced the protein levels of S100A7. Transactivation activity of 5′-upstream regions of S100A7 was activated by Stat3 but was reduced by treatment with Lu, Qu, SU6656 and S3I-201. The treatment also reduced the migratory and invasive abilities of A431-III cells. In a further analysis of EMT markers, the protein level of E-cad increased and that of Twist decreased after treatment with the inhibitors and flavonoids. Overexpression of S100A7 decreased the protein level of E-cad and increased the Twist level, whereas knockdown of S100A7 had the opposite effects. Treatment with S3I-201, Lu and Qu, compared to the control, were found to decrease metastasis of tumor cells in zebrafish larvae. These results suggest that Lu and Qu may inhibit Src/Stat3/S100A7 signaling to reduce tumorigenesis of cancer cells. View Full-Text
Keywords: luteolin; quercetin; S100A7; Src; Stat3; metastasis luteolin; quercetin; S100A7; Src; Stat3; metastasis
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Fan, J.-J.; Hsu, W.-H.; Lee, K.-H.; Chen, K.-C.; Lin, C.-W.; Lee, Y.-L.A.; Ko, T.-P.; Lee, L.-T.; Lee, M.-T.; Chang, M.-S.; Cheng, C.-H. Dietary Flavonoids Luteolin and Quercetin Inhibit Migration and Invasion of Squamous Carcinoma through Reduction of Src/Stat3/S100A7 Signaling. Antioxidants 2019, 8, 557.

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