Abstract
BackgroundA number of homeobox genes have been implicated in the development of various cancers. However, the role of engrailed 2 (EN2), a member of the homeobox gene superfamily, in esophageal squamous cell carcinoma (ESCC) remains unknown.MethodsThe expression of EN2 was examined using quantitative real-time PCR and immunohistochemistry. A stable cell line was established to express exogenous EN2 using a lentivirus system. The malignant phenotype was analyzed with proliferation, clonogenicity, wound-healing and invasion assays. The CRISPR/Cas9 system was adopted to deplete endogenous EN2. RNA profiling was performed using gene expression microarray. The ShRNA-mediated method was used to knock down the expression of SPARC. The structure-function relationship was determined using site-directed mutagenesis.ResultsEN2 is highly expressed in ESCC. The malignant phenotype of the ESCC cell line was amplified by an overexpression of EN2 but was attenuated by a disruption of EN2. RNA profiling analysis revealed that distinct sets of genes were modulated by the expression of EN2 in various ESCC cell lines and oncogenes were among these. EN2 greatly increased the expression of SPARC in Eca109. Site-directed mutagenesis revealed that the induction of SPARC was closely correlated with the protumor function of EN2. ShRNA-mediated knockdown of SPARC attenuated the malignant phenotype of EN2-infected cells. These data suggest that SPARC is crucial for mediating the protumor function of EN2.DiscussionEN2 has an oncogenic function in ESCC that is mediated by upregulating the expression of pro-oncogenic genes downstream. EN2 may potentially act as a diagnostic marker or therapeutic target for ESCC treatment in the future.
Highlights
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies diagnosed in China and worldwide and is associated with high rates of morbidity andHow to cite this article Cao Y, Wang X, Tang L, Li Y, Song X, Liu X, Li M, Chen F, Wan H. 2020
engrailed 2 (EN2) is highly expressed in esophageal squamous cell carcinoma (ESCC) tissues Engrailed-2, a member of the homeobox superfamily, is highly expressed in a number of cancers, including cancers of the bladder, prostate, and breast (Bose, Bullard & Donald, 2008; Martin et al, 2005; Morgan et al, 2011, 2013)
Surgical specimens derived from ESCC patients were used to examine the expression level of EN2 using quantitative real-time polymerase chain reaction to support these results
Summary
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies diagnosed in China and worldwide and is associated with high rates of morbidity andHow to cite this article Cao Y, Wang X, Tang L, Li Y, Song X, Liu X, Li M, Chen F, Wan H. 2020. Engrailed-2 promotes a malignant phenotype of esophageal squamous cell carcinoma through upregulating the expression of pro-oncogenic genes. The role of engrailed 2 (EN2), a member of the homeobox gene superfamily, in esophageal squamous cell carcinoma (ESCC) remains unknown. The malignant phenotype of the ESCC cell line was amplified by an overexpression of EN2 but was attenuated by a disruption of EN2. RNA profiling analysis revealed that distinct sets of genes were modulated by the expression of EN2 in various ESCC cell lines and oncogenes were among these. ShRNA-mediated knockdown of SPARC attenuated the malignant phenotype of EN2-infected cells. These data suggest that SPARC is crucial for mediating the protumor function of EN2. Discussion: EN2 has an oncogenic function in ESCC that is mediated by upregulating the expression of pro-oncogenic genes downstream. EN2 may potentially act as a diagnostic marker or therapeutic target for ESCC treatment in the future
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