Post-transcriptional Regulation of the EMT Program Depends on HuR and is Associated with Worse Survival in Pancreatic Cancer Patients

Abstract

Purpose: It has been suggested that HuR is involved in the post-transcriptional regulation of the Epithelial-mesenchymal transition (EMT) program through major EMT-activating transcription factors (EMT-TFs) as Snail1, Snail2, ZEB1, ZEB2, TWIST. However, the impact of HuR on post-transcriptional regulation of EMT-TFs and their impact on carcinogenesis in the pancreatic adenocarcinoma (PDAC) still remains unclear. The purpose of our study is to assess the role of transcription factor HuR on the EMT-TFs and to determine the association with clinicopathological parameters and prognosis of PDAC. Methods: Data of 45 patients after pancreatodeduodenectomy for PDAC between 2009- 2017 were analyzed. Patient’s mRNA expression levels of Snail, Snail2, ZEB1, ZEB2 and TWIST in PDAC were compared with normal pancreatic tissue. The correlations among EMT-TFs with clinicopathological parameters were analyzed. The Kaplan-Meier method and log-rank tests were used for univariate analysis. Pancreatic cancer cell line BxPC-3 was transfected with anti-HuR siRNR and RT-PCR analysis was carried out for EMT-TFs expression. Results: Snail1, Snail2, ZEB1 and Twist expression were accordingly 1643.05 fold, 2186.02-fold, 1723.33-fold and 3.72-fold higher, while ZEB2 expression were 0.53-fold lower when compared to normal pancreatic tissue. Univariate analysis revealed that high expression of all EMT-TFs was associated with worse overall survival (0S) of PDAC patients. High expression levels of ZEB1 were associated with peripancreatic invasion. Following siHuR transfection, the upregulation of EMT-TFs expression was observed. Conclusion: Our results suggests that upregulation of HuR significantly affects EMT program in the pancreatic cancer cell lines and might be related with poor outcomes in PDAC patients.