Oncogenic K-RAS is required to maintain changes in cytoskeletal organization, adhesion, and motility in colon cancer cells
Oncogenic K-RAS is required to maintain changes in cytoskeletal organization, adhesion, and motility in colon cancer cells
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DOI：
10.1158/0008-5472.can-04-1911
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发表时间：
2005-02-15
期刊：
影响因子：
11.2
通讯作者：
Dhillon, AS
中科院分区：
文献类型：
--
作者：
Pollock, CB;Shirasawa, S;Dhillon, AS
RAS 癌基因被认为在肿瘤发生的多个阶段发挥作用。 RAS 癌基因维持人类癌细胞转化状态的作用和机制尚不清楚。在这里，我们研究了致癌 K-RAS 在维持转移性结肠癌细胞的细胞骨架破坏、细胞粘附和运动中的作用。从 HCT116 结肠癌细胞中定向删除 K-RAS（G13D）可恢复其组装应力纤维和粘着斑/复合物的能力，同时伴随着细胞-基质粘附力的增强和运动性的降低。我们进一步表明，致癌 K-Ras 诱导高 Rho 活性，但使 Rho 与应力纤维形成脱钩。这种解偶联需要通过丝裂原激活蛋白/细胞外信号调节激酶依赖性途径维持高水平的激活蛋白-1家族成员Fra-I。我们还表明，致癌 K-Ras 下游的 HCT116 细胞的运动需要 PI3 激酶信号传导。我们的研究结果表明，突变的 K-RAS 癌基因对于维持人类结肠癌细胞的转化和侵袭表型至关重要。
RAS oncogenes are thought to play a role at multiple stages of tumorigenesis. The role and mechanisms by which RAS oncogenes maintain the transformed state of human cancer cells are poorly understood. Here, we have studied the role of oncogenic K-RAS in maintaining cytoskeletal disruption, cell adhesion and motility in metastatic colon carcinoma cells. Targeted deletion of K-RAS(G13D) from HCT116 colon carcinoma cells restored their ability to assemble stress fibers and focal adhesions/complexes, accompanied by increased cell-matrix adhesion and reduced motility. We further show that oncogenic K-Ras induces high Rho activity, but uncouples Rho from stress fiber formation. This uncoupling required the maintenance of high levels of the activator protein-1 family member, Fra-I, via a mitogen-activated protein/extracellular signal-regulated kinase-dependent pathway. We also show that PI3-kinase signaling is required for the motility of HCT116 cells downstream of oncogenic K-Ras. Our findings suggest that mutated K-RAS oncogenes are essential for maintenance of the transformed and invasive phenotype of human colon cancer cells.