Decreased expression of ATF3, orchestrated by β-catenin/TCF3, miR-17-5p and HOXA11-AS, promoted gastric cancer progression via increased β-catenin and CEMIP.

ATF3 has been reported to be dysregulated in various cancers and involved in various steps of tumorigenesis. However, the mechanisms underlying the abnormal expression of ATF3 and its biological function in gastric cancer (GC) have not been well investigated. Here, we report ATF3 as one of the key regulators of GC development and progression. Patients with low ATF3 expression had shorter survival and a poorer prognosis. In vitro and in vivo assays investigating ATF3 alterations revealed a complex integrated phenotype that affects cell growth and migration. Strikingly, high-throughput sequencing and microarray analysis of cells with ATF3 silencing or of ATF3-low GC tissues indicated alterations in the Wnt signaling pathway, focal adhesions and adherens junctions. Mechanistically, the expression of β-catenin and cell migration inducing hyaluronidase 1 (CEMIP) was significantly upregulated in GC cells with downregulated ATF3, which was synergistically repressed by the β-catenin/TCF3 signaling axis and noncoding RNA miR-17-5p and HOXA11-AS. In addition, we found that WDR5 expression was promoted by TCF3 and is involved in miR-17-5p and HOXA11-AS activation in GC cells. Taken together, our findings revealed the mechanism of ATF3 downregulation and its biological role in regulating the expression of Wnt signaling-related genes during GC progression, suggesting new informative biomarkers of malignancy and therapeutic directions for GC patients. New treatments for gastric cancer could involve controlling the activity of a regulatory gene and associated signaling pathway. Over-activation of the Wnt signaling pathway, which regulates many cellular functions, occurs in around half of gastric cancers. Further, the activating transcription factor 3 gene (ATF3) is thought to influence tumorigenesis, although its role in gastric cancer is unclear. Guohua Xie and co-workers at Shanghai Jiao Tong University, China, explored the function of ATF3 in human gastric cancer tissues. Patients with low ATF3 expression had poorer prognosis and shorter life expectancy. The team discovered that reduced expression of ATF3 triggered the increased expression of two of its target genes, which then altered Wnt signaling. Reduced ATF3 expression also boosted the invasiveness of gastric cancer cells. Initial results suggest that overexpression of ATF3 could suppress gastric cancer progression.