期刊
CANCER LETTERS
卷 407, 期 -, 页码 66-75出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.08.001
关键词
P-REX1; Melanoma; PAK1/p38/MMP-2; Copy number
类别
资金
- National Institute of Health
- National Cancer Institute [1R01CA167967-01A1]
- Adelson Medical Research Foundation
- China National Natural Science Foundation [81573454]
- Beijing Natural Science Foundation [7172142]
- CAMS Innovation Fund for Medical Sciences (CIFMS) [2016-I2M-3-007]
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 PREX1 shRNA, proliferation, colony formation, 3D matrigel growth, and migration/invasiveness were inhibited. Loss of P-REX1 inhibited cell proliferation by inhibiting cyclin Dl, 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. (C) 2017 Published by Elsevier B.V.
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