Medical Clinic D, Medical Cell Biology, University Hospital of Münster, Münster, Germany.
Cancer Gene Ther. 2023 Mar;30(3):497-506. doi: 10.1038/s41417-022-00570-2. Epub 2022 Dec 9.
Downregulation of cell-cell adhesion and increased motility are prerequisites for the metastasis of cancer cells. We have recently shown that downregulation of the tight junction adapter protein Pals1 in colorectal cancer cells results in an increase of cell migration, invasion, and metastasis due to the enhanced activation of Arf6 and Rac1. We now reveal a redundancy between the Arf6-GAP SMAP1 and Pals1 in regulating Arf6 activity and thereby Rac1-dependent cell migration. The gene encoding SMAP1 is frequently disrupted in microsatellite instable colorectal cancer specimen and cell lines. In cells expressing SMAP1, deletion of Pals1 leads to disturbed formation of tight junctions but has no impact on Arf6 activity and cell migration. In contrast, inactivation of both SMAP1 and Pals1 results in enhanced Arf6/Rac1 activity and increased cell migration and invasion. Furthermore, analyzing patient cohorts, we found a significant decrease in patient's survival when both genes were downregulated, in contrast to cases, when expression of only one of both genes was affected. Taken together, we identified a redundancy between SMAP1 and Pals1 in the regulation of activation of Arf6/Rac1, thereby controlling cell migration, invasion, and metastasis of colorectal cancer cells.
细胞-细胞黏附的下调和迁移能力的增强是癌细胞转移的前提条件。我们最近表明，结直肠癌细胞中紧密连接接头蛋白 Pals1 的下调会导致细胞迁移、侵袭和转移增加，这是由于 Arf6 和 Rac1 的激活增强。我们现在揭示了 Arf6-GAP SMAP1 和 Pals1 在调节 Arf6 活性以及 Rac1 依赖性细胞迁移方面的冗余性。编码 SMAP1 的基因在微卫星不稳定的结直肠癌细胞标本和细胞系中经常被破坏。在表达 SMAP1 的细胞中，缺失 Pals1 会导致紧密连接的形成受到干扰，但对 Arf6 活性和细胞迁移没有影响。相比之下，SMAP1 和 Pals1 的同时失活会导致 Arf6/Rac1 活性增强，细胞迁移和侵袭增加。此外，通过分析患者队列，我们发现当两个基因都下调时，患者的生存率显著降低，而当只有一个基因受到影响时，情况则相反。总之，我们发现 SMAP1 和 Pals1 在调节 Arf6/Rac1 的激活方面存在冗余性，从而控制结直肠癌细胞的迁移、侵袭和转移。
