Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, 02447, South Korea.
Division of Molecular Biology, College of Pharmacy, Kyung Hee University, Seoul, 02447, South Korea.
Sci Rep. 2017 Aug 22;7(1):9076. doi: 10.1038/s41598-017-08880-4.
Missense mutations of TP53 are extremely common, and mutant p53 accumulation and gain-of-function play crucial roles in human ovarian cancer. Here, we investigated the role of mutant p53 in cell migration and invasion as well as its underlying molecular mechanisms in human ovarian cancer cells. Overexpression of mutant p53 significantly increased migration and invasion in p53-null SKOV3 cells. In contrast, knockdown of mutant p53 significantly compromised mutant p53-induced cell migration and invasion. Microarray analysis revealed that several migration/invasion-related genes, including S1PR1 (Sphingosine-1-phosphate receptor 1) and THBS1 (Thrombospodin 1), were significantly upregulated in SKOV3 cells that overexpressed mutant p53-R248 (SKOV3). We found that Rad21 is involved in the transcriptional regulation of the migration/invasion-related genes induced by mutant p53-R248. Knockdown of Rad21 significantly attenuated the mutant p53-R248-induced invasion and the expressions of S1PR1 and THBS1. Moreover, co-immunoprecipitation and chromatin immunoprecipitation assays revealed that mutant p53 interacts with Rad21 and binds to the Rad21-binding elements in the S1PR1 and THBS1 genes. Finally, downregulation of S1PR1 significantly attenuated the invasion driven by mutant p53-R248. These novel findings reveal that mutant p53-R248 maintains gain-of-function activity to stimulate cell invasion and induces the related gene expressions through an interaction with Rad21 in human ovarian cancer cells.
TP53 的错义突变极其常见，突变型 p53 的积累和获得功能在人类卵巢癌中起着至关重要的作用。在这里，我们研究了突变型 p53 在人卵巢癌细胞迁移和侵袭中的作用及其潜在的分子机制。过表达突变型 p53 可显著增加 p53 缺失的 SKOV3 细胞的迁移和侵袭。相反，敲低突变型 p53 可显著削弱突变型 p53 诱导的细胞迁移和侵袭。微阵列分析显示，几种迁移/侵袭相关基因，包括 S1PR1（鞘氨醇-1-磷酸受体 1）和 THBS1（血栓素 1），在过表达突变型 p53-R248 的 SKOV3 细胞中显著上调。我们发现 Rad21 参与了突变型 p53-R248 诱导的迁移/侵袭相关基因的转录调控。Rad21 的敲低显著减弱了突变型 p53-R248 诱导的侵袭以及 S1PR1 和 THBS1 的表达。此外，共免疫沉淀和染色质免疫沉淀实验表明，突变型 p53 与 Rad21 相互作用，并结合 S1PR1 和 THBS1 基因中的 Rad21 结合元件。最后，下调 S1PR1 可显著减弱突变型 p53-R248 驱动的侵袭。这些新发现揭示了突变型 p53-R248 通过与 Rad21 相互作用，维持获得功能活性以刺激细胞侵袭，并在人卵巢癌细胞中诱导相关基因表达。
