Lv Tao, Wu Xianqiang, Sun Lijuan, Hu Qingyong, Wan Yang, Wang Liang, Zhao Zhiqiang, Tu Xiao, Xiao Zhi-Xiong Jim
Center of Growth, Metabolism and Aging, and Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China.
Cell Death Dis. 2017 Aug 10;8(8):e2995. doi: 10.1038/cddis.2017.376.
Mounting evidence indicates that hotspot p53 mutant proteins often possess gain-of-function property in promoting cell mobility and tumor metastasis. However, the molecular mechanisms are not totally understood. In this study, we demonstrate that the hotspot mutation, p53-R273H, promotes cell migration, invasion in vitro and tumor metastasis in vivo. p53-R273H significantly represses expression of DLX2, a homeobox protein involved in cell proliferation and pattern formation. We show that p53-R273H-mediated DLX2 repression leads to upregulation of Neuropilin-2 (NRP2), a multifunctional co-receptor involved in tumor initiation, growth, survival and metastasis. p53-R273H-induced cell mobility is effectively suppressed by DLX2 expression. Furthermore, knockdown of NRP2 significantly inhibits p53-R273H-induced tumor metastasis in xenograft mouse model. Together, these results reveal an important role for DLX2-NRP2 in p53-R273H-induced cell mobility and tumor metastasis.
越来越多的证据表明，热点p53突变蛋白在促进细胞迁移和肿瘤转移方面通常具有功能获得性特性。然而，其分子机制尚未完全明确。在本研究中，我们证明热点突变p53-R273H促进细胞体外迁移、侵袭以及体内肿瘤转移。p53-R273H显著抑制DLX2的表达，DLX2是一种参与细胞增殖和模式形成的同源框蛋白。我们发现p53-R273H介导的DLX2抑制导致神经纤毛蛋白-2（NRP2）上调，NRP2是一种参与肿瘤起始、生长、存活和转移的多功能共受体。DLX2表达可有效抑制p53-R273H诱导的细胞迁移。此外，在异种移植小鼠模型中，敲低NRP2可显著抑制p53-R273H诱导的肿瘤转移。总之，这些结果揭示了DLX2-NRP2在p53-R273H诱导的细胞迁移和肿瘤转移中的重要作用。
