Genistein suppresses FLT4 and inhibits human colorectal cancer metastasis.
Genistein suppresses FLT4 and inhibits human colorectal cancer metastasis.
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金雀异黄素抑制FLT4并抑制人结直肠癌转移
DOI：
10.18632/oncotarget.3064
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发表时间：
2015-02-20
期刊：
影响因子：
--
通讯作者：
Fan D
中科院分区：
文献类型：
--
作者：
Xiao X;Liu Z;Wang R;Wang J;Zhang S;Cai X;Wu K;Bergan RC;Xu L;Fan D
饮食中摄入大豆中发现的染料木黄酮与结直肠癌（CRC）发展和进展中的潜在保护作用有关。在此，我们证明了染料木黄酮将抑制人CRC细胞的侵袭和迁移，它在非细胞毒性浓度下这样做，并且我们在多种人CRC细胞系中证明了这一点。将人CRC肿瘤原位植入小鼠后，口服染料木黄酮不能抑制肿瘤生长，但能抑制远处转移形成，并且对小鼠无毒。使用qPCR阵列，我们筛选了染料木黄酮诱导的基因表达变化，随后通过Western印迹确认，证明染料木黄酮下调基质金属蛋白酶2和Fms相关酪氨酸激酶4（FLT 4;血管内皮生长因子受体3）。在证明染料木黄酮抑制小鼠肿瘤中的新血管生成后，我们检测了来自60名人类受试者的原发性CRC和邻近正常结肠组织中的FLT 4表达，证明FLT 4的增加与分期增加和存活率降低显著相关。总之，我们第一次证明染料木黄酮在饮食、无毒剂量下抑制人CRC转移。FLT 4被鉴定为转移性疾病的标志物，并且作为抑制CRC转移的小分子治疗剂的应答标志物。
Dietary consumption of genistein, found in soy, has been associated with a potentially protective role in colorectal cancer (CRC) development and progression. Herein we demonstrate that genistein will inhibit human CRC cell invasion and migration, that it does so at non-cytotoxic concentrations and we demonstrate this in multiple human CRC cell lines. After orthotopic implantation of human CRC tumors into mice, oral genistein did not inhibit tumor growth, but did inhibit distant metastasis formation, and was non-toxic to mice. Using a qPCR array, we screened for genistein-induced changes in gene expression, followed by Western blot confirmation, demonstrating that genistein downregulated matrix metalloproteinase 2 and Fms-Related Tyrosine Kinase 4 (FLT4; vascular endothelial growth factor receptor 3). After demonstrating that genistein suppressed neo-angiogenesis in mouse tumors, we examined FLT4 expression in primary CRC and adjacent normal colonic tissue from 60 human subjects, demonstrating that increased FLT4 significantly correlates with increased stage and decreased survival. In summary, we demonstrate for the first time that genistein inhibits human CRC metastasis at dietary, non-toxic, doses. FLT4 is identified as a marker of metastatic disease, and as a response marker for small molecule therapeutics that inhibit CRC metastasis.
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