FOXC2 promotes colorectal cancer metastasis by directly targeting MET (Retracted article. See vol. 41, pg. 2529, 2022)
FOXC2 promotes colorectal cancer metastasis by directly targeting MET (Retracted article. See vol. 41, pg. 2529, 2022)
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FOXC2直接靶向MET促进结直肠癌转移
DOI：
10.1038/onc.2014.368
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发表时间：
2015-08-13
期刊：
影响因子：
8
通讯作者：
Ding, Y-Q
中科院分区：
文献类型：
--
作者：
Cui, Y-M;Jiao, H-L;Ding, Y-Q
转移是结直肠癌(CRC)的主要死亡原因。尽管目前已发现多种基因参与了结直肠癌的发生发展，但使结直肠癌细胞发生早期局部侵袭和形成远处转移集落的分子机制仍不十分清楚。在此，我们研究了叉头盒蛋白C2(FOXC2)在结直肠癌侵袭和转移中的作用，并探讨其可能的机制。我们发现FOXC2的高表达和FOXC2的核定位与晚期TNM分期(T=原发肿瘤；N=区域淋巴结；M=远处转移)显著相关。FOXC2可增强结直肠癌细胞的体外侵袭能力，促进结直肠癌小鼠原位转移模型的局部侵袭和远处转移。基因芯片分析显示，FOXC2的过表达增加了原癌基因MET酪氨酸激酶的表达，并激活了肝细胞生长因子(HGF)-MET信号通路。此外，荧光素酶报告实验和染色质免疫沉淀实验表明FOXC2直接与MET启动子结合，从而增加MET的转录活性。抑制MET可减弱FOXC2过表达的CRC细胞的侵袭表型和转移潜能，提示MET是FOXC2促进转移的主要介质。此外，结直肠癌组织中FOXC2的表达与MET的表达呈正相关。我们的研究结果表明，FOXC2通过诱导MET的表达来调节HGF-MET信号转导，从而在结直肠癌转移中发挥重要作用，提示FOXC2是预防或减少结直肠癌转移的潜在治疗靶点。
Metastasis is the major cause of death in colorectal cancer (CRC). Although multiple genes have been identified to be responsible for the development of CRC, the molecular changes that enable CRC cells to undergo early local invasion and to form distant metastatic colonies still remain largely unknown. Herein, we investigated the role of Forkhead box protein C2 (FOXC2) and explored the underlying mechanisms in invasion and metastasis of CRC. We show that both high FOXC2 expression and nuclear localization of FOXC2 are significantly correlated with advanced TNM (T=primary tumor; N=regional lymph nodes; M=distant metastasis) stages. FOXC2 enhanced the invasive abilities of CRC cells in vitro and promoted local invasion and distant metastasis in an orthotopic mouse metastatic model of CRC. Microarray analysis revealed that overexpression of FOXC2 increased the proto-oncogene MET tyrosine kinase expression and activated the hepatocyte growth factor (HGF)-MET signaling pathway. Furthermore, luciferase reporter assays and chromatin immunoprecipitation assays revealed that FOXC2 directly associated with MET promoter to increase the transcriptional activity of MET. Inhibition of MET attenuates the invasive phenotype and metastatic potential of FOXC2-overexpressing CRC cells, indicating that MET is a major mediator of FOXC2-promoted metastasis. In addition, FOXC2 expression was positively correlated with MET expression in CRC tissue samples. Our findings suggest that FOXC2 has a crucial role in CRC metastasis by regulating HGF-MET signaling via inducing MET expression, highlighting FOXC2 as a potential therapeutic target for preventing or reducing metastasis in CRC.