Identification of aberrantly expressed F-box proteins in squamous-cell lung carcinoma.

Purpose: F-box proteins, as components of the Skp1-Cullin 1-F-box protein (SCF) E3 ubiquitin ligase, can specifically bind to substrates and regulate multiple tumor behaviors. However, the role of F-box proteins in squamous-cell lung carcinoma (SqCLC) has not been established.

Methods: We identified the differentially expressed F-box protein-encoding genes in SqCLC by analyzing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Prognosis data were evaluated using the Kaplan-Meier (KM) plotter website. The FBXO5 and FBXO45 mRNA levels were analyzed by real time RT-PCR. The impact of the inhibition of these genes with si-RNA on apoptosis and migration was also investigated.

Results: The FBXO45 and FBXO5 genes were significantly up-regulated in SqCLC compared with normal lung (p values = 0.002 and 0.025, respectively). FBXO45 was significantly elevated in each tumorigenic step, including dysplasia, in situ and SqCLC. The RT-PCR analysis results showed that FBXO5 and FBXO45 were elevated in cancer tissues (p values = 0.024 and 0.004, respectively). Overexpression of FBXO5 and FBXO45 was associated with shorter overall survival (OS) in the SqCLC patients from the K-M plotter database [FBXO5 HR: 1.53 (1.03-2.28), p = 0.036]; [FBXO45 HR: 1.47 (1.03-2.08), p = 0.030]. The GO and KEGG pathway analysis showed that FBXO5 and FBXO45 were associated with cell cycle and adhesion, respectively. Knockdown of FBXO5 leads to increased apoptosis, while knockdown of FBXO45 facilitates the process of epithelial-mesenchymal transition (EMT).

Conclusions: Our results provide evidence that FBXO45 and FBXO5 may play a key role in tumorigenesis and prognosis of SqCLC.