ESE1/AGR2 axis antagonizes TGF-β-induced epithelial-mesenchymal transition in low-grade pancreatic cancer

Epithelium-specific ETS transcription factor 1 (ESE1) has been implicated in epithelial homeostasis, inflammation, as well as tumorigenesis, and cancer progression. However, numerous studies have reported contradictory roles-as an oncogene or a tumor suppressor of ESE1 in different cancers, and its function in the development and progression of pancreatic ductal adenocarcinoma (PDAC) has remained largely unexplored. Herein, we report that ESE1 was found upregulated in primary PDAC compared to normal pancreatic tissue, but high expression of ESE1 correlated to better relapse-free survival in patients with PDAC. Interestingly, ESE1 was found to exhibit dual roles in regulation of malignant properties of PDAC cells in that its overexpression promoted cell proliferation, whereas its downregulation enhanced epithelial-mesenchymal transition (EMT) phenotype. In the context of TGF-beta-induced EMT, ESE1 is markedly downregulated at post-transcriptional level, and reconstituted ESE1 expression partially reversed TGF-beta-induced EMT marker expression. Furthermore, we identify AGR2 as a novel transcriptional target of ESE1 that participates in TGF-beta-induced EMT in PDAC. Collectively, our findings reveal an ESE1/AGR2 axis that interacts with TGF-beta signaling to modulate EMT phenotype in PDAC.

Automated summary

The epithelium-specific ETS transcription factor 1 (ESE1) has been found to be upregulated in primary pancreatic ductal adenocarcinoma (PDAC). Interestingly, high expression of ESE1 is associated with better relapse-free survival in PDAC patients. ESE1 exhibits dual roles in regulating malignant properties of PDAC cells by promoting cell proliferation when overexpressed and enhancing epithelial-mesenchymal transition (EMT) phenotype when downregulated. ESE1 interacts with TGF-beta signaling to modulate EMT phenotype in PDAC.