P-REX1 amplification promotes progression of cutaneous melanoma via the PAK1/P38/MMP-2 pathway.
P-REX1 amplification promotes progression of cutaneous melanoma via the PAK1/P38/MMP-2 pathway.
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DOI：
10.1016/j.canlet.2017.08.001
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发表时间：
2017-10
期刊：
影响因子：
9.7
通讯作者：
Jinhua Wang;H. Hirose;Guanhua Du;K. Chong;E. Kiyohara;I. Witz;D. Hoon
中科院分区：
文献类型：
--
作者：
Jinhua Wang;H. Hirose;Guanhua Du;K. Chong;E. Kiyohara;I. Witz;D. Hoon
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GDP交换与Rac结合的GTP来激活Rac。P-REX1表达异常上调在黑色素瘤转移中起作用，但P-REX1在皮肤黑色素瘤中的拷贝数（CN）和功能尚不清楚。为了探索P-REX1在黑色素瘤中的作用，我们对SNP 6.0和Exon 1.0 ST微阵列进行了评估。P-REX1在黑色素瘤细胞中的CN比在黑色素细胞中高（变化2.82倍），P-REX1的表达与P-REX1 CN显著相关。当P-REX1 shRNA在细胞中敲除P-REX1时，增殖、集落形成、3D基质生长和迁移/侵袭性均受到抑制。P-REX1的缺失通过抑制细胞周期蛋白D1抑制细胞增殖，阻断细胞周期，并通过降低survivin蛋白的表达增加细胞凋亡。敲低P-REX1表达可通过破坏P-REX1/RAC1/PAK1/p38/MMP-2通路抑制细胞迁移/侵袭。对患者肿瘤和疾病结局的评估显示，与P-REX1低表达的患者相比，高表达的AJCC I/II/III期患者的无远处转移生存率较低。这些结果表明P-REX1在肿瘤进展中起重要作用，是潜在的治疗靶点。
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.