Oncotarget, 2014, 6(5):3225-39.

Genistein suppresses FLT4 and inhibits human colorectal cancer metastasis

Xiao Xiao, Zhiguo Liu, Rui Wang, et al

State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China

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.

美国《肿瘤靶标》, 2014, 6(5):3225-39.

金雀异黄素抑制 FLT4 并抑制人体大肠癌转移
肖骁，刘志国，王睿，等

北京市，西安市，第四军医大学，西京医院，消化病医院，肿瘤生物与西京医院国家重点实验室

在大豆中发现的染料木素与结肠直肠癌（CRC）发展和进展中的潜在保护作用相关。在这里我们证明染料木素将抑制人类的CRC细胞入侵和迁移，我们证明这在多个人类的CRC细胞系没有细胞毒性。在将人CRC肿瘤原位植入小鼠后，口服染料木黄酮不抑制肿瘤生长，但确实抑制远处转移形成，并且对小鼠无毒。使用qPCR阵列，我们筛选染料木素诱导的基因表达的变化，随后是蛋白质印迹确认，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（FLT4;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，我们检查了来自60个人受试者的原发性CRC和相邻正常结肠组织中的FLT4表达，证明增加的FLT4与增加的阶段和减少的存活显着相关。总之，我们第一次证明染料木黄酮抑制饮食，无毒，剂量的人类CRC转移。 FLT4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。