The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Target Research, Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
Department of Translational Medicine, Division Molecular Oncology, John Wayne Cancer Institute (JWCI) at Providence Saint John's Health Center, Santa Monica, CA 90404, USA.
Cancer Lett. 2017 Oct 28;407:66-75. doi: 10.1016/j.canlet.2017.08.001. Epub 2017 Aug 10.
P-REX1 (PIP3-dependent Rac exchange factor-1) is a guanine nucleotide exchange factor that activates Rac by catalyzing exchange of GDP for GTP bound to Rac. Aberrant up-regulation of P-REX1 expression has a role in metastasis however, copy number (CN) and function of P-REX1 in cutaneous melanoma are unclear. To explore the role of P-REX1 in melanoma, SNP 6.0 and Exon 1.0 ST microarrays were assessed. There was a higher CN (2.82-fold change) of P-REX1 in melanoma cells than in melanocytes, and P-REX1 expression was significantly correlated with P-REX1 CN. When P-REX1 was knocked down in cells by P-REX1 shRNA, proliferation, colony formation, 3D matrigel growth, and migration/invasiveness were inhibited. Loss of P-REX1 inhibited cell proliferation by inhibiting cyclin D1, blocking cell cycle, and increased cell apoptosis by reducing expression of the protein survivin. Knockdown of P-REX1 expression inhibited cell migration/invasiveness by disrupting P-REX1/RAC1/PAK1/p38/MMP-2 pathway. Assessment of patient tumors and disease outcome demonstrated lower distant metastasis-free survival among AJCC stage I/II/III patients with high P-REX1 expression compared to patients with low P-REX1 expression. These results suggest P-REX1 plays an important role in tumor progression and a potential theranostic target.
P-REX1（PIP3 依赖性 Rac 交换因子-1）是一种鸟嘌呤核苷酸交换因子，通过催化 Rac 结合的 GDP 与 GTP 的交换来激活 Rac。P-REX1 表达的异常上调在转移中起作用，然而，P-REX1 在皮肤黑色素瘤中的拷贝数（CN）和功能尚不清楚。为了探讨 P-REX1 在黑色素瘤中的作用，评估了 SNP 6.0 和 Exon 1.0 ST 微阵列。与黑素细胞相比，黑色素瘤细胞中的 P-REX1 CN 更高（2.82 倍变化），并且 P-REX1 表达与 P-REX1 CN 显著相关。当 P-REX1 通过 P-REX1 shRNA 在细胞中被敲低时，增殖、集落形成、3D 基质胶生长和迁移/侵袭能力受到抑制。P-REX1 的缺失通过抑制细胞周期蛋白 D1、阻断细胞周期以及通过降低蛋白 survivin 的表达来增加细胞凋亡，从而抑制细胞增殖。敲低 P-REX1 表达通过破坏 P-REX1/RAC1/PAK1/p38/MMP-2 通路来抑制细胞迁移/侵袭。对患者肿瘤和疾病结果的评估表明，与 P-REX1 低表达的 AJCC 分期 I/II/III 患者相比，P-REX1 高表达的患者远处无转移生存率较低。这些结果表明 P-REX1 在肿瘤进展中发挥重要作用，是一个有潜力的治疗靶点。
