Document Type

Journal Article

Department/Unit

School of Chinese Medicine

Language

English

Abstract

Background: Melanoma is notorious for its propensity to metastasize, which makes treatment extremely difficult. Receptor tyrosine kinase c-Met is activated in human melanoma and is involved in melanoma progression and metastasis. Hepatocyte growth factor (HGF)-mediated activation of c-Met signaling has been suggested as a therapeutic target for melanoma metastasis. Quercetin is a dietary flavonoid that exerts anti-metastatic effect in various types of cancer including melanoma. In a previous report, we demonstrated that quercetin inhibited melanoma cell migration and invasion in vitro, and prevented melanoma cell lung metastasis in vivo. In this study, we sought to determine the involvement of HGF/c-Met signaling in the anti-metastatic action of quercetin in melanoma. Methods: Transwell chamber assay was conducted to determine the cell migratory and invasive abilities. Western blotting was performed to determine the expression levels and activities of c-Met and its downstream molecules. And immunoblotting was performed in BS3 cross-linked cells to examine the homo-dimerization of c-Met. Quantitative real-time PCR analysis was carried out to evaluate the mRNA expression level of HGF. Transient transfection was used to overexpress PAK or FAK in cell models. Student's t-test was used in analyzing differences between two groups. Results: Quercetin dose-dependently suppressed HGF-stimulated melanoma cell migration and invasion. Further study indicated that quercetin inhibited c-Met phosphorylation, reduced c-Met homo-dimerization and decreased c-Met protein expression. The effect of quercetin on c-Met expression was associated with a reduced expression of fatty acid synthase. In addition, quercetin suppressed the phosphorylation of c-Met downstream molecules including Gab1 (GRB2-associated-binding protein 1), FAK (Focal Adhesion Kinase) and PAK (p21-activated kinases). More importantly, overexpression of FAK or PAK significantly reduced the inhibitory effect of quercetin on the migration of the melanoma cells. Conclusions: Our findings suggest that suppression of the HGF/c-Met signaling pathway contributes to the anti-metastatic action of quercetin in melanoma.

Keywords

C-Met, Invasion, Melanoma, Metastasis, Migration, Quercetin

Publication Date

12-2015

Source Publication Title

Molecular Cancer

Volume

14

Start Page

103

Publisher

BioMed Central

Peer Reviewed

1

Copyright

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver applies to the data made available in this article, unless otherwise stated.

Funder

This work was supported by the Research Grants Council of Hong Kong (HKBU 262512); Food and Health Bureau of Hong Kong (HMRF 11122521); Science, Technology and Innovation Commission of Shenzhen (JCYJ20120829154222473 and JCYJ20140807091945050); and the Hong Kong Baptist University (FRG1/14- 15/061 and FRG2/14-15/056).

DOI

10.1186/s12943-015-0367-4

Link to Publisher's Edition

http://dx.doi.org/10.1186/s12943-015-0367-4

ISSN (print)

14764598

ISSN (electronic)

14764598

Additional Files

JA-5163-28199_suppl_Figure S1.tiff (202 kB)

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