FARP1 boosts CDC42 activity from integrin αvβ5 signaling and correlates with poor prognosis of advanced gastric cancer

Takuro Hirano, Yoshinari Shinsato, Kan Tanabe, Nayuta Higa, Muhammad Kamil, Kohichi Kawahara, Masatatsu Yamamoto, Kentaro Minami, Michiko Shimokawa, Takaaki Arigami, Shigehiro Yanagita, Daisuke Matushita, Yoshikazu Uenosono, Sumiya Ishigami, Yuko Kijima, Kosei Maemura, Ikumi Kitazono, Akihide Tanimoto, Tatsuhiko Furukawa, Shoji Natsugoe

Research output: Contribution to journalArticlepeer-review

Abstract

Considering the poor prognosis of most advanced cancers, prevention of invasion and metastasis is essential for disease control. Ras homologous (Rho) guanine exchange factors (GEFs) and their signaling cascade could be potential therapeutic targets in advanced cancers. We conducted in silico analyses of The Cancer Genome Atlas expression data to identify candidate Rho-GEF genes showing aberrant expression in advanced gastric cancer and found FERM, Rho/ArhGEF, and pleckstrin domain protein 1 (FARP1) expression is related to poor prognosis. Analyses in 91 clinical advanced gastric cancers of the relationship of prognosis and pathological factors with immunohistochemical expression of FARP1 indicated that high expression of FARP1 is significantly associated with lymphatic invasion, lymph metastasis, and poor prognosis of the patients (P = 0.025). In gastric cancer cells, FARP1 knockdown decreased cell motility, whereas FARP1 overexpression promoted cell motility and filopodium formation via CDC42 activation. FARP1 interacted with integrin β5, and a potent integrin αvβ5 inhibitor (SB273005) prevented cell motility in only high FARP1-expressing gastric cancer cells. These results suggest that the integrin αvβ5-FARP1-CDC42 axis plays a crucial role in gastric cancer cell migration and invasion. Thus, regulatory cascade upstream of Rho can be a specific and promising target of advanced cancer treatment.

Original languageEnglish
Article number13
JournalOncogenesis
Volume9
Issue number2
DOIs
Publication statusPublished - 01-02-2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

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