P-REX1 amplification promotes progression of cutaneous melanoma via the PAK1/P38/MMP-2 pathway

Jinhua Wang, Hajime Hirose, Guanhua Du, Kelly Chong, Eiji Kiyohara, Isaac P. Witz, Dave S.B. Hoon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)66-75
Number of pages10
JournalCancer Letters
Volume407
DOIs
StatePublished - 28 Oct 2017

Funding

FundersFunder number
D.H.
National Institutes of Health
National Cancer InstituteR01CA167967
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
Innovation Skills Fund
National Natural Science Foundation of China81573454
Chinese Academy of Meteorological Sciences2016-I2M-3-007
Natural Science Foundation of Beijing Municipality7172142

    Keywords

    • Copy number
    • Melanoma
    • P-REX1
    • PAK1/p38/MMP-2

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