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

Research output: Contribution to journalArticlepeer-review

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

Keywords

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

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