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

Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan
Food and Drug Administration, Ministry of Health and Welfare, Taipei 11561, Taiwan
Department of Surgery, Wan-Fang Hospital, Taipei Medical University, Taipei 11034, Taiwan
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11034, Taiwan
Cancer Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11034, Taiwan
Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11034, Taiwan
Departments of Medicine and Pediatrics, Duke University Hospital, Durham, NC 27704, USA
Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan
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;
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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