Journal Article FBXO50 Enhances the Malignant Behavior of Gastric Cancer Cells

Miwa, Takashi  ,  Kanda, Mitsuro  ,  Tanaka, Haruyoshi  ,  Tanaka, Chie  ,  Kobayashi, Daisuke  ,  Umeda, Shinichi  ,  Iwata, Naoki  ,  Hayashi, Masamichi  ,  Yamada, Suguru  ,  Fujii, Tsutomu  ,  Fujiwara, Michitaka  ,  Kodera, Yasuhiro

24 ( 12 )  , pp.3771 - 3779 , 2017-11 , Springer
BackgroundChallenges to our understanding the molecular mechanisms of the progression of gastric cancer (GC) must be overcome to facilitate the identification of novel biomarkers and therapeutic targets. In this article, we analyzed the expression of the gene encoding F-box-only 50 (FBXO50) and determined whether it contributes to the malignant phenotype of GC.\nMethodsFBXO50 messenger RNA (mRNA) levels and copy numbers of the FBXO50 locus were determined in 10 GC cell lines and a nontumorigenic epithelial cell line. Polymerase chain reaction array analysis was performed to identify genes coordinately expressed with FBXO50. The effects of inhibiting FBXO50 on GC cell proliferation, adhesion, invasiveness, and migration were evaluated using a small interfering RNA targeted to FBXO50 mRNA. To evaluate the clinical significance of FBXO50 expression, we determined the levels of FBXO50 mRNA in tissues acquired from 200 patients with GC.\nResultsThe levels of FBXO50 mRNA were increased in five GC cell lines and positively correlated with those of ITGA5, ITGB1, MMP2, MSN, COL5A2, GNG11, and WNT5A. Copy number gain of the FBXO50 locus was detected in four GC cell lines. Inhibition of FBXO50 expression significantly decreased the proliferation, adhesion, migration, and invasiveness of GC cell lines. In clinical samples, high FBXO50 expression correlated with increased pT4, invasive growth, lymph node metastasis, and positive peritoneal lavage cytology. Patients with high FBXO50 expression had a significantly higher prevalence of recurrence after curative gastrectomy and were more likely to experience shorter overall survival.\nConclusionsFBXO50 may represent a biomarker for GC phenotypes and as a target for therapy.\nElectronic supplementary materialThe online version of this article (doi: 10.1245/s10434-017-5882-7) contains supplementary material, which is available to authorized users.Despite its declining incidence, gastric cancer (GC) is the fifth most frequent cancer and the third leading cause of cancer-related death worldwide.1 Although therapeutic strategies have improved, the 5-year survival rates of patients with GC are <30%.2,3 Metastasis and disease recurrence are two major obstacles to increasing long-term survival, and early intervention is required.4,5 A better understanding of the molecular mechanisms of GC progression is therefore required to identify biomarkers and therapeutic targets to improve diagnosis and treatment strategies.\nF-box proteins contain at least one F-box domain that mediates protein–protein interactions and is associated with signal transduction and the regulation of the cell cycle.6, 7, 8 Little evidence is available that illuminates the role of genes that encode F-box only proteins (FBXO). For example, FBXO28 controls Myc-dependent transcription, is regulated during the cell cycle by cyclin-dependent kinase 1/2-mediated phosphorylation, and overexpression of FBXO28 is strongly associated with poor prognosis of patients with breast cancer.9 We identified F-box-only 50 (FBXO50; alternatively called non-specific cytotoxic cell receptor protein 1, NCCRP1) as a gene that is aberrantly expressed in metastatic GC by our previous transcriptome analysis.10,11 However, to our knowledge, no study reports the analysis of the expression and function of FBXO50 in GC.12\nThese findings led us to hypothesize that FBXO50 is associated with the malignant phenotype of GC. Therefore, the present study was conducted to analyze the expression of FBXO50 in GC tissues and cell lines and to determine whether FBXO50 enhances the malignant phenotype of GC cells.

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