Fascin, a novel target of β-Catenin-TCF signaling, is expressed at the invasive front of human colon cancer
Fascin, a novel target of β-Catenin-TCF signaling, is expressed at the invasive front of human colon cancer
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DOI：
10.1158/0008-5472.can-07-0929
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发表时间：
2007-07-15
期刊：
影响因子：
11.2
通讯作者：
Robine, Sylvie
中科院分区：
文献类型：
--
作者：
Vignjevic, Danijela;Schoumacher, Marie;Robine, Sylvie
癌细胞通过获得运动和侵袭性表型而转移。这一步需要肌动蛋白细胞骨架的重塑和被称为丝状伪足的探索性、感应器的表达。β-连环蛋白-TCF靶基因的异常激活在结直肠癌的发生发展中起重要作用。我们发现丝状伪足的关键成分Socor1是结直肠癌细胞β-连环蛋白-TCF信号转导的靶点。Fascin1mRNA和蛋白在原发癌组织中的表达呈分期依赖性增加。Fascin1仅定位于肿瘤的侵袭性前沿，也表达核β-连环蛋白。在结直肠癌细胞中强制表达PENCE1增加了其在细胞培养中的迁移和侵袭，并在体内引起了细胞的扩散和转移，而小干扰RNA抑制SENCE1的表达则减少了细胞的侵袭。虽然在原发灶中的表达与转移有关，但在转移灶中不表达。我们的研究表明，这令人着迷。在结肠癌转移过程中，其表达受到严格调控，是β-连环蛋白-TCF信号转导的新靶点。我们认为，在结直肠癌中，SENCE1基因的瞬时上调促进了导致转移的迁移和侵袭表型的获得。此外，当肿瘤细胞到达其转移的目的地，停止迁移和促进增殖时，ZONCE1的表达被下调。虽然转移到重要器官通常是死亡的原因，但在开发针对转移疾病的有效治疗方法方面取得的成功有限。我们认为，参与细胞迁移和侵袭的基因，如Socor1，可以作为预防转移的新靶点。
Cancer cells become metastatic by acquiring a motile and invasive phenotype. This step requires remodeling of the actin cytoskeleton and the expression of exploratory, sensor organelles known as filopodia. Aberrant beta-catenin-TCF target gene activation plays a major role in colorectal cancer development. We identified fascin1, a key component of filopodia, as a target of beta-catenin-TCF signaling in colorectal cancer cells. Fascin1 mRNA and protein expression were increased in primary cancers in a stage-dependent manner. Fascin1 was exclusively localized at the invasive front of tumors also displaying nuclear beta-catenin. Forced expression of fascin1 in colorectal cancer cells increased their migration and invasion in cell cultures and caused cell dissemination and metastasis in vivo, whereas suppression of fascin1 expression by small interfering RNA reduces cell invasion. Although expression of fascin1 in primary tumors correlated with the presence of metastases, fascin1 was not expressed in metastases. Our studies show that fascin1. expression is tightly regulated during development of colon cancer metastases and is a novel target of beta-catenin-TCF signaling. We propose that transient up-regulation of fascin1 in colorectal cancer promotes the acquisition of migratory and invasive phenotypes that lead to metastasis. Moreover, the expression of fascin1 is down-regulated when tumor cells reach their metastatic destination where migration ceases and proliferation is enhanced. Although metastasis to vital organs is often the cause of mortality, only limited success has been attained in developing effective therapeutics against metastatic disease. We propose that genes involved in cell migration and invasion, such as fascin1, could serve as novel targets for metastasis prevention.