TY - JOUR
T1 - FARP1 boosts CDC42 activity from integrin αvβ5 signaling and correlates with poor prognosis of advanced gastric cancer
AU - Hirano, Takuro
AU - Shinsato, Yoshinari
AU - Tanabe, Kan
AU - Higa, Nayuta
AU - Kamil, Muhammad
AU - Kawahara, Kohichi
AU - Yamamoto, Masatatsu
AU - Minami, Kentaro
AU - Shimokawa, Michiko
AU - Arigami, Takaaki
AU - Yanagita, Shigehiro
AU - Matushita, Daisuke
AU - Uenosono, Yoshikazu
AU - Ishigami, Sumiya
AU - Kijima, Yuko
AU - Maemura, Kosei
AU - Kitazono, Ikumi
AU - Tanimoto, Akihide
AU - Furukawa, Tatsuhiko
AU - Natsugoe, Shoji
N1 - Funding Information:
The authors thank Dr. Hiroshi Okumura for his useful advice; Ms. Naoko Hidaka and Ms. Izumi Minamimagari for their excellent secretarial assistance; and Ms. Chieri Nakayama, Ms. Rie Tajiri, Ms. Mika Tokunaga, Ms. Maki Motomura, Ms. Aya Harada, and Ms. Tomoko Takajo for their excellent technical assistance. We also wish to thank the Joint Research Laboratory, Kagoshima University Graduate School of Medical and Dental Sciences, for allowing us to use their facilities, as well as Editage (www.editage.jp) for English language editing. This work was supported by Japan Society for the Promotion of Science (JSPS)
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41389-020-0190-7
DO - 10.1038/s41389-020-0190-7
M3 - Article
AN - SCOPUS:85079033428
VL - 9
JO - Oncogenesis
JF - Oncogenesis
SN - 2157-9024
IS - 2
M1 - 13
ER -