Loss of apical-basal polarity and downregulation of cell-cell contacts is a critical step during the pathogenesis of cancer. Both processes are regulated by the scaffolding protein Pals1, however, it is unclear whether the expression of Pals1 is affected in cancer cells and whether Pals1 is implicated in the pathogenesis of the disease. Using mRNA expression data and immunostainings of cancer specimen, we show that Pals1 is frequently downregulated in colorectal cancer, correlating with poorer survival of patients. We further found that Pals1 prevents cancer cell metastasis by controlling Rac1-dependent cell migration through inhibition of Arf6, which is independent of the canonical binding partners of Pals1. Loss of Pals1 in colorectal cancer cells results in increased Arf6 and Rac1 activity, enhanced cell migration and invasion in vitro and increased metastasis of transplanted tumor cells in mice. Thus, our data reveal a new function of Pals1 as a key inhibitor of cell migration and metastasis of colorectal cancer cells. Notably, this new function is independent of the known role of Pals1 in tight junction formation and apical-basal polarity.

中文翻译：

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Pals1 通过抑制 Arf6 防止 Rac1 依赖性结直肠癌细胞转移

顶端 - 基底极性的丧失和细胞 - 细胞接触的下调是癌症发病机制中的关键步骤。这两个过程都受支架蛋白 Pals1 的调节，然而，尚不清楚 Pals1 的表达是否在癌细胞中受到影响，以及 Pals1 是否与疾病的发病机制有关。使用癌症标本的 mRNA 表达数据和免疫染色，我们显示 Pals1 在结直肠癌中经常下调，与患者的较差生存率相关。我们进一步发现 Pals1 通过抑制 Arf6 来控制 Rac1 依赖性细胞迁移来防止癌细胞转移，Arf6 独立于 Pals1 的典型结合伙伴。结直肠癌细胞中 Pals1 的缺失导致 Arf6 和 Rac1 活性增加，增强体外细胞迁移和侵袭，增加小鼠移植肿瘤细胞的转移。因此，我们的数据揭示了 Pals1 作为结直肠癌细胞细胞迁移和转移的关键抑制剂的新功能。值得注意的是，这一新功能独立于 Pals1 在紧密连接形成和顶端-基底极性中的已知作用。