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.
Highlights
Molecular targeted therapies have successfully improved prognoses of several patients with cancer; prognoses of most patients carrying advanced cancers are still poor
The Cancer Genome Atlas (TCGA) data analysis indicated that the gene expression of TRIO, NET1, ECT2, TIAM2, FARP1, ARHGEF12 and BCR in primary cancer was significantly higher than those in normal tissues (Supplementary Fig. S1)
We showed that FARP1 overexpression was significantly associated with lymphatic invasion, lymph metastasis, and poor prognosis in patients with advanced gastric cancer, and that it promoted gastric cancer cell motility by activating CDC42
Summary
Molecular targeted therapies have successfully improved prognoses of several patients with cancer; prognoses of most patients carrying advanced cancers are still poor. Trastuzumab (a HER2neutralizing antibody) and ramucirumab (an anti-VEGFR2 antibody) have been introduced with or without combined treatment of cytotoxic agents that have improved the survival of patients with gastric cancer; the. Better management of advanced cancers, including gastric cancer, through the use of new targeted therapeutic agents, is urgently required. Rho family proteins comprises 20 members in humans as a major branch of the Ras superfamily of small GTPases that regulate actin organization, cell motility, polarity, growth, survival, and gene transcription[1,12]. Rho GTPases are crucial for cancer cell migration, invasion, and metastasis[13]. Mutations of Ras genes have been identified in over 30% of human cancers[14]; very few mutations in Rho GTPases have been detected
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