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.

Details

Title
FARP1 boosts CDC42 activity from integrin αvβ5 signaling and correlates with poor prognosis of advanced gastric cancer
Author
Hirano Takuro 1 ; Shinsato Yoshinari 2 ; Tanabe Kan 3 ; Higa Nayuta 4 ; Kamil Muhammad 4 ; Kawahara Kohichi 2 ; Yamamoto Masatatsu 2 ; Minami Kentaro 2 ; Shimokawa Michiko 2 ; Arigami Takaaki 5   VIAFID ORCID Logo  ; Yanagita Shigehiro 3 ; Matushita Daisuke 3 ; Uenosono Yoshikazu 3 ; Ishigami Sumiya 3 ; Kijima Yuko 3 ; Maemura Kosei 3 ; Kitazono Ikumi 6 ; Tanimoto Akihide 7 ; Furukawa Tatsuhiko 8   VIAFID ORCID Logo  ; Natsugoe Shoji 9 

1  Kagoshima University Graduate School of Medical and Dental Sciences, Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801); Kagoshima University Graduate School of Medical and Dental Sciences, Department of Molecular Oncology, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801) 
2  Kagoshima University Graduate School of Medical and Dental Sciences, Department of Molecular Oncology, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801) 
3  Kagoshima University Graduate School of Medical and Dental Sciences, Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801) 
4  Kagoshima University Graduate School of Medical and Dental Sciences, Department of Molecular Oncology, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801); Kagoshima University Graduate School of Medical and Dental Sciences, Department of Neurosurgery, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801) 
5  Kagoshima University Graduate School of Medical and Dental Sciences, Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801); Kagoshima University Graduate School of Medical and Dental Sciences, Onco-Biological Surgery, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801) 
6  Kagoshima University Graduate School of Medical and Dental Sciences, Department of Pathology, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801) 
7  Kagoshima University, Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801); Kagoshima University Graduate School of Medical and Dental Sciences, Department of Pathology, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801) 
8  Kagoshima University Graduate School of Medical and Dental Sciences, Department of Molecular Oncology, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801); Kagoshima University, Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801) 
9  Kagoshima University Graduate School of Medical and Dental Sciences, Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801); Kagoshima University Graduate School of Medical and Dental Sciences, Onco-Biological Surgery, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801); Kagoshima University, Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801) 
Publication year
2020
Publication date
Feb 2020
Publisher
Nature Publishing Group
e-ISSN
21579024
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41389-020-0190-7
ProQuest document ID
2352045898
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.