Silencing the MET oncogene leads to regression of experimental tumors and metastases
Silencing the MET oncogene leads to regression of experimental tumors and metastases
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DOI：
10.1038/sj.onc.1210697
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发表时间：
2008-01-24
期刊：
影响因子：
8
通讯作者：
Giordano, S.
中科院分区：
文献类型：
--
作者：
Corso, S.;Migliore, C.;Giordano, S.
尽管对癌症发病的基因改变已经有了一定的了解，但促进和维持侵袭/转移表型的基因仍然是难以捉摸的。MET原癌基因编码肝细胞生长因子（HGF）酪氨酸激酶受体，感知不利的微环境条件并驱动细胞侵袭和转移。MET过表达，通常由肿瘤缺氧诱导，导致受体的组成性激活，并与不良预后相关。为了确定MET在肿瘤进展的不同阶段中的作用，我们开发了一种可诱导的慢病毒RNA干扰传递系统。抑制肿瘤细胞中过度表达的内源性MET基因会导致(i)体外完全侵袭性生长程序的执行受损，（ii）肿瘤生长缺乏，（iii）体内实验转移的产生减少。值得注意的是，在已经建立的转移中，沉默MET导致它们几乎完全消退。这表明MET癌基因的持续表达是强制性的，直到癌症进展的晚期。
In spite of the established knowledge of the genetic alterations responsible for cancer onset, the genes promoting and maintaining the invasive/metastatic phenotype are still elusive. The MET proto-oncogene, encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF), senses unfavorable micro-environmental conditions and drives cell invasion and metastasis. MET overexpression, often induced by tumor hypoxia, leads to constitutive activation of the receptor and correlates with poor prognosis. To establish the role of MET in different phases of tumor progression, we developed an inducible lentiviral delivery system of RNA interference. Silencing the endogenous MET gene, overexpressed in tumor cells, resulted in (i) impairment of the execution of the full invasive growth program in vitro, (ii) lack of tumor growth and (iii) decreased generation of experimental metastases in vivo. Notably, silencing MET in already established metastases led to their almost complete regression. This indicates that persistent expression of the MET oncogene is mandatory until the advanced phases of cancer progression.