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

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.

FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma

“…FARP1 has been mostly involved in neuronal development, particularly in the control of synaptogenesis, dendritic filopodial dynamics, and branching Biederer, 2012, 2014), and more recently in the regulation of endothelial integrity (Amado-Azevedo et al, 2017). A recent report showed FARP1 to boost Cdc42 activity and filopodia formation in advanced gastric cancer (Hirano et al, 2020), an observation that we were unable to observe in lung adenocarcinoma cells (unpublished data). The consistent impairment in membrane ruffling activity and Rac1/PAK activation in FARP1-depleted lung adenocarcinoma cells upon the stimulation of multiple RTKs strongly advocates for its role as a positive regulator of a Rac1 centered signaling unit, as suggested in neuronal models (Cheadle and Biederer, 2012).…”

Methylation silencing CDH23 is a poor prognostic marker in diffuse large B-cell lymphoma

“…Overexpression of FARP1 was significantly correlated with lymph metastasis, lymphatic invasion and poor prognosis in advanced gastric cancer patients. FARP1 promoted cell motility through activating CDC42 in gastric cancer [ 24 ]. MYO3A was reported to serve as a prognostic marker for tracking progression of breast cancer toward metastasis [ 25 ].…”

Upregulation of FGD6 Predicts Poor Prognosis in Gastric Cancer

“…It was reported that knockdown of CDC42 inhibited the proliferation, migration, and invasion of GC cells ( 21 ). Moreover, studies have found that FARP1 binds to integrin αvβ5 and promotes GC cell migration and invasion through the activation of CDC42 ( 22 ). Recently, a study has shown that aberrant expression of CDC42 in colorectal cancer can cause the migration, invasion, and metastasis through activation of the VEGF/NRP1 axis and is closely related to the prognosis of the patients ( 23 ).…”