Abstract
BackgroundThe Ecotropic viral integration site 5 (Evi5) is recognized as a potential oncogene and a cell cycle regulator. Evi5 regulates the abundance of Emi1, an inhibitor of the anaphase-promoting complex/cyclosome, to govern mitotic fidelity. Evi5 has been shown to be dysregulated in several cancer types. However, the expression and biological function of Evi5 in human laryngeal squamous cell carcinoma (LSCC) are still unknown.MethodsClustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing was used to generate Evi5 knockout (KO) LSCC cells. The proliferation and cell cycle distribution of LSCC cells was determined. The effect of Evi5 on LSCC tumor growth in vivo was studied in a tumor xenograft model in mice. The interaction between Evi5 and c-Myc was detected by immunoprecipitation (IP) assay. Luciferase assay was used to determine the transcriptional activity of c-Myc.ResultsHere, we show that Evi5 controls LSCC tumorigenesis via the stabilization of c-MYC oncogene. CRISPR-mediated knockout (KO) of Evi5 decreased the proliferation and decreased colony formation ability of LSCC cells. Knockout of Evi5 caused increased G1 phase and decreased S phase cells. In the tumor-bearing nude mice, The transplanted tumors originated from Evi5-KO TU212 cells were significantly decreased when compared with control TU212 cells. At the molecular level, we found that Evi5 interacted with c-MYC and Evi5 antagonized E3 ligase FBXW7-mediated ubiquitination and degradation of c-Myc protein, and promoted c-Myc-dependent transactivation.ConclusionGiven the critical role of c-Myc in tumorigenesis, our data suggest that Evi5 is a potential therapeutic target in LSCC, and inhibition of Evi5 should be a prospective strategy for LSCC therapy.
Highlights
The Ecotropic viral integration site 5 (Evi5) is recognized as a potential oncogene and a cell cycle regu‐ lator
Evi5 is required for laryngeal squamous cell carcinoma (LSCC) cells proliferation both in vitro and in vivo To investigate whether Evi5 affects the proliferation of LSCC cells, we silenced the expression of Evi5 in LSCC TU212 cells used two small hairpin RNA against different regions of Evi5
Our data demonstrate that the Evi5FBXW7-c-Myc regulatory axis serves a role in the regulation of LSCC cell proliferation in vitro and tumorigenesis in vivo. These findings suggest that Evi5 is a potential therapeutic target in LSCC, and inhibition of Evi5 is the prospective strategy for LSCC therapy
Summary
The Ecotropic viral integration site 5 (Evi5) is recognized as a potential oncogene and a cell cycle regu‐ lator. The expression and biologi‐ cal function of Evi in human laryngeal squamous cell carcinoma (LSCC) are still unknown. Laryngeal carcinoma is the most common cancer in the larynx and the second most common malignant tumor of the respiratory system. Laryngeal squamous cell carcinoma (LSCC) is the major type for laryngeal carcinoma (about 95%) [2]. Genetic studies found that oncogene c-Myc is related to the event of laryngeal cancer [5]. Overexpression of c-Myc promotes cell growth, proliferation, apoptosis, transformation, premessenger-RNA splicing and genomic instability [7]. DNA methylation of MYCT1 altered the promoter activity by interfering with its binding to c-Myc in LSCC [9]. Overexpression of MYCT1 could inhibit cell proliferation and invasion and promote apoptosis in LSCC cells [10]. It is warranted to better understand the molecular mechanisms underlying LSCC tumorigenesis and to identify the novel therapeutic targets for LSCC treatment
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