Cell invasion allows cells to migrate across compartment boundaries formed by basement membranes. Aberrant cell invasion is a first step during the formation of metastases by malignant cancer cells. Anchor cell (AC) invasion in C. elegans is an excellent in vivo model to study the regulation of cell invasion during development. Here, we have examined the function of egl-43, the homolog of the human Evi1 proto-oncogene (also called MECOM), in the invading AC. egl-43 plays a dual role in this process, firstly by imposing a G1 cell cycle arrest to prevent AC proliferation, and secondly, by activating pro-invasive gene expression. We have identified the AP-1 transcription factor fos-1 and the Notch homolog lin-12 as critical egl-43 targets. A positive feedback loop between fos-1 and egl-43 induces pro-invasive gene expression in the AC, while repression of lin-12 Notch expression by egl-43 ensures the G1 cell cycle arrest necessary for invasion. Reducing lin-12 levels in egl-43 depleted animals restored the G1 arrest, while hyperactivation of lin-12 signaling in the differentiated AC was sufficient to induce proliferation. Taken together, our data have identified egl-43 Evi1 as an important factor coordinating cell invasion with cell cycle arrest.

细胞侵袭允许细胞跨越由基底膜形成的隔室边界迁移。异常细胞侵袭是恶性癌细胞形成转移过程的第一步。C 中的锚细胞 (AC) 侵袭。elegans是一种极好的体内模型，用于研究发育过程中细胞侵袭的调节。在这里，我们检查了egl-43的功能，它是人类Evi1原癌基因（也称为MECOM）的同源物，在入侵的 AC 中。egl-43在这个过程中发挥双重作用，首先通过强制 G1 细胞周期停滞以防止 AC 增殖，其次通过激活促侵袭基因表达。我们已将 AP-1 转录因子fos-1和Notch同源物lin-12 确定为关键的egl-43目标。fos-1和egl-43之间的正反馈回路诱导 AC 中的促侵袭基因表达，而egl-43对lin-12 Notch表达的抑制确保了侵袭所需的 G1 细胞周期停滞。降低egl-43耗竭动物的lin-12水平可恢复 G1 期阻滞，同时分化的 AC 中的lin-12信号足以诱导增殖。总之，我们的数据已将egl-43 Evi1确定为协调细胞侵袭与细胞周期停滞的重要因素。