Clinical significance of ZNF750 gene expression, a novel tumor suppressor gene, in esophageal squamous cell carcinoma

Abstract

Abstract. The present authors previously identified a novel candidate tumor suppressor gene, zinc finger protein 750 (ZNF750), in esophageal squamous cell carcinoma (ESCC) (1). The present study aimed to clarify the clinical significance of ZNF750 expression in ESCC. The association between ZNF750 DNA mutation status and the mRNA expression was examined by whole exome sequence analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR). The expression of ZNF750 in 76 patients with ESCC (Kyushu University Beppu Hospital) was measured using immunohistochemistry and RT-qPCR. Using this dataset, the association between ZNF750 mRNA expression and clinicopathological factors was examined. Additionally, survival analysis was performed using datasets from the Kyushu University Beppu Hospital and The Cancer Genome Atlas (TCGA). The biological effects of ZNF750 expression were explored using gene set enrichment analysis (GSEA) and were validated using datasets from the Cancer Cell Line Encyclopedia (CCLE) and the Kyushu University Beppu Hospital. ZNF750 expression analyses demonstrated that ZNF750 mRNA expression was lower in patients with the DNA mutations compared with those without the mutations (P<0.05), and ZNF750 expression was downregulated in tumor tissues compared with normal tissues (P<0.00005). In the clinicopathological analysis, the low ZNF750 expression group exhibited a higher incidence of undifferentiated histology (P<0.05) compared with the high expression group. The low ZNF750 expression group exhibited a poorer prognosis in the Kyushu and TCGA datasets (P<0.0005 and P<0.05, respectively). GSEA indicated that ZNF750 expression was significantly correlated with epithelial differentiation in ESCC. This was confirmed using the datasets from CCLE and the Kyushu University Beppu Hospital by analyzing the levels of small proline rich protein 1A mRNA, an epithelial differentiation-associated gene. In conclusion, the results of the present study suggested that ZNF750 serves a role as a tumor suppressor; potentially via regulating epithelial differentiation and that it may be a promising biomarker of poor outcomes in ESCC.

The clinical significance of collagen family gene expression in esophageal squamous cell carcinoma

“…Recently, studies have found that the expression of certain genes, such as MCT4, ZNF750, Gli1, etc. was highly related to the occurrence and development of ESCC, and they might be applied as ideal biomarkers for ESCC (Cheng et al, 2018; Nambara et al, 2017; Yang et al, 2017; Zhang et al, 2018b). In addition, the aberrant expression of a few collagen family genes has also been reported to be significantly associated with the prognosis of ESCC patients.…”

Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

“…Analysis of cancer genes across 21 tumor types identified ZNF750 as a gene harboring many early frameshift and nonsense mutations in head and neck cancer and as the only known gene residing in a small current focal deletion in head and neck and lung squamous cancers ( Lawrence et al, 2014 ). ZNF750 has also been identified as a tumor suppressor in oral and esophageal squamous cell carcinoma ( Yang et al, 2017 ; Nambara et al, 2017 ; Hazawa et al, 2017 ; Otsuka et al, 2018 ). Studies on the clonal evolution in esophageal squamous cell carcinoma revealed that the majority of driver mutations in this cancer occurred in the tumor-suppressor genes, including TP53, KMT2D , and ZNF750 ( Hao et al, 2016 ).…”

ZNF750 inhibits the proliferation and invasion of melanoma cells through modulating the Wnt/b-catenin signaling pathway

“…In oral squamous cell carcinoma, ZNF750 inhibited cell migration, invasion, and decreased the expression of matrix metalloproteinase 28, cyclin B1 and mesenchymal marker neural cadherin [24], and also have been reported to inhibit the malignant progression by regulating tumor vascular microenvironment [9]. In addition, in esophageal squamous cell carcinoma, low expression of ZNF750 was demonstrated to be closely related to the resistance to chemoradiotherapy, positive lymph node metastasis, and poor prognosis [11,25], and downregulation of ZNF750 increased cell growth, migration, and invasion [8]. In other non-squamous cell carcinomas such as nasopharyngeal carcinomas, ZNF750 has also been shown to have an inhibitory effect on malignant tumor progression [7].…”