TLE2 is associated with favorable prognosis and regulates cell growth and gemcitabine sensitivity in pancreatic cancer

Abstract

BACKGROUND: The transducin-like enhancer of split (TLE) proteins are a group of transcriptional corepressors. They play a crucial role in cellular homeostasis and are involved in various cancers. Compared with other TLE family members, little is known about the role and the underlying mechanism of TLE2 in human cancers. This study aimed to investigate the role of TLE2 in pancreatic ductal adenocarcinoma (PDAC) using in silico analysis and in vitro experiments. METHODS: Data were obtained from the Cancer Genome Atlas (TCGA) database to evaluate the prognostic value of TLE2 in PDAC. The MiaPaCa-2 cell line was transfected with siRNA to inhibit endogenous TLE2 expression, and a PANC-1 cell line with stable TLE2 overexpression was constructed using lentiviral transfection, which were confirmed by real-time polymerase chain reaction and western blotting. MTT assay, transwell invasion assays, and flow cytometry were carried out to assess cell viability, invasion, and apoptosis, respectively. TLE2 expression in PDAC cells was altered to evaluate their sensitivity to gemcitabine. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to predict the biological role of TLE2. RESULTS: High expression of TLEs was significantly associated with increased overall survival (OS) and disease-free survival (DFS) in patients with PDAC. Among the PDAC cell lines, TLE2 expression was lowest and highest in PANC-1 cells and MiaPaCa-2 cells, respectively. TLE2 overexpression impaired the proliferation ability of PANC-1 cells and downregulation of TLE2 promoted the proliferation of MiaPaCa-2 cells. Upregulation of TLE2 in PANC-1 cells induced S-phase accumulation and sensitivity to gemcitabine. In contrast, the downregulation of TLE2 in MiaPaCa-2 cells promoted resistance to gemcitabine. Moreover, bioinformatics analysis also revealed the potential tumor suppressor role of TLE2 and uncovered a close relationship between TLE2 expression and cell cycle regulation. CONCLUSIONS: Our results suggest that TLE2 expression is correlated with prognosis in patients with PDAC and show that TLE2 plays a central role in the regulation of cell proliferation, the cell cycle, and gemcitabine sensitivity. This study provides new insights and evidence that TLE2 functions as a tumor suppressor gene and prognostic marker in PDAC.