Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United states of America.
Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United states of America.
PLoS One. 2019 Feb 1;14(2):e0202065. doi: 10.1371/journal.pone.0202065. eCollection 2019.
Loss of function of the tumor suppressor p53 is known to increase the rate of migration of cells transiting the narrow pores of the traditional Boyden chamber assay. Here by contrast we investigate how p53 impacts the rate of cellular migration within a 2D confluent cell layer and a 3D collagen-embedded multicellular spheroid. We use two human carcinoma cell lines, the bladder carcinoma EJ and the colorectal carcinoma HCT116. In the confluent 2-D cell layer, for both EJ and HCT cells the migratory speeds and effective diffusion coefficients for the p53 null cells were significantly smaller than in p53-expressing cells. Compared to p53 expressers, p53-null cells exhibited more organized cortical actin rings together with reduced front-rear cell polarity. Furthermore, loss of p53 caused cells to exert smaller traction forces upon their substrates, and reduced formation of cryptic lamellipodia. In the 3D multicellular spheroid, loss of p53 consistently reduced collective cellular migration into surrounding collagen matrix. As regards the role of p53 in cellular migration, extrapolation from the Boyden chamber assay to other cellular microenvironments is seen to be fraught even in terms of the sign of the effect. Together, these paradoxical results show that the effects of p53 on cellular migration are context-dependent.
已知肿瘤抑制因子 p53 的失活会增加细胞通过传统 Boyden 室测定的狭窄孔的迁移率。相比之下，我们研究了 p53 如何影响二维细胞层和三维胶原嵌入的多细胞球体中细胞迁移的速度。我们使用两种人癌细胞系，膀胱癌 EJ 和结直肠癌 HCT116。在 2-D 细胞层中，对于 EJ 和 HCT 细胞，p53 缺失细胞的迁移速度和有效扩散系数明显小于 p53 表达细胞。与 p53 表达细胞相比，p53 缺失细胞表现出更有组织的皮质肌动蛋白环，同时细胞前后极性降低。此外，p53 的缺失导致细胞对其底物施加的牵引力减小，并减少了隐斑的形成。在 3D 多细胞球体中，p53 的缺失一致降低了细胞向周围胶原基质的集体迁移。关于 p53 在细胞迁移中的作用，即使从 Boyden 室测定推断到其他细胞微环境，也存在效应的符号甚至都不确定的问题。总之，这些矛盾的结果表明，p53 对细胞迁移的影响是依赖于上下文的。
