Quercetin inhibits HGF/c-Met signaling and HGF-stimulated melanoma cell migration and invasion.
Quercetin inhibits HGF/c-Met signaling and HGF-stimulated melanoma cell migration and invasion.
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DOI：
10.1186/s12943-015-0367-4
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发表时间：
2015-05-14
期刊：
影响因子：
37.3
通讯作者：
Yu ZL
中科院分区：
文献类型：
--
作者：
Cao HH;Cheng CY;Su T;Fu XQ;Guo H;Li T;Tse AK;Kwan HY;Yu H;Yu ZL
黑色素瘤因其转移倾向而臭名昭著，这使得治疗极其困难。受体酪氨酸激酶c-Met在人类黑色素瘤中被激活，并参与黑色素瘤的进展和转移。肝细胞生长因子(HGF)介导的c-Met信号的激活已被认为是黑色素瘤转移的治疗靶点。槲皮素是一种饮食中的类黄酮类化合物，对包括黑色素瘤在内的各种癌症具有抗转移作用。在之前的一篇报道中，我们证明了槲皮素在体外抑制黑色素瘤细胞的迁移和侵袭，并在体内阻止黑色素瘤细胞的肺转移。在这项研究中，我们试图确定HGF/c-Met信号通路是否参与了Qercetin对黑色素瘤的抗转移作用。Transwell小室实验检测细胞的迁移和侵袭能力。Western blotting检测c-Met及其下游分子的表达水平和活性。免疫印迹法检测BS3细胞c-Met的同源二聚化情况。实时荧光定量聚合酶链式反应检测肝细胞生长因子的基因表达水平。瞬时转染法在细胞模型中过表达PAK或FAK。采用t检验分析两组间的差异。Quercetin剂量依赖地抑制HGF刺激的黑色素瘤细胞迁移和侵袭。进一步的研究表明，槲皮素抑制c-Met的磷酸化，减少c-Met的同源二聚化，降低c-Met蛋白的表达。槲皮素对c-Met表达的影响与减少脂肪酸合成酶的表达有关。此外，Quercetin还抑制c-Met下游分子的磷酸化，包括GAB1(Grb2相关结合蛋白1)、FAK(粘着斑激酶)和PAK(p21激活的激酶)。更重要的是，FAK或PAK的过表达显著降低了Quercetin对黑色素瘤细胞迁移的抑制作用。我们的研究结果表明，抑制HGF/c-Met信号通路参与了Qercetin对黑色素瘤的抗转移作用。本文的在线版本(doi：10.1186/s12943-0150367-4)包含补充材料，授权用户可以使用。
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. 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. 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. Our findings suggest that suppression of the HGF/c-Met signaling pathway contributes to the anti-metastatic action of quercetin in melanoma. The online version of this article (doi:10.1186/s12943-015-0367-4) contains supplementary material, which is available to authorized users.
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影响因子：
8
作者：
Bigelow, RLH;Cardelli, JA
通讯作者：
Cardelli, JA
DOI：
10.1073/pnas.0403390101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Menendez, JA;Vellon, L;Lupu, R
通讯作者：
Lupu, R
影响因子：
7.5
作者：
Kapur, P;Rakheja, D;Hoang, MP
通讯作者：
Hoang, MP
影响因子：
3.8
作者：
de Andrade, B. A. B.;Leon, J. E.;de Almeida, O. P.
通讯作者：
de Almeida, O. P.
影响因子：
4
作者：
Loizzo, Monica Rosa;Said, Ataa;Menichini, Francesco
通讯作者：
Menichini, Francesco