Abstract
Background Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) serves as an effector for tumor growth in human malignancies. However, the mechanism of ERO1L on promoting metastasis of pancreatic ductal adenocarcinoma (PDAC) remains to be further explored. Methods Bioinformatics analysis of public databases and large-scale metastatic PDAC sequencing was performed to determine the expression profile and prognostic value of ERO1L in PDAC. The effect of ERO1L on metastasis of PDAC was analyzed in vitro and in vivo, via cell biological, molecular, and biochemical approaches. Results ERO1L in PDAC hepatic metastatic tissues were highly expressed and related to disease-free survival (DFS). Genetic silencing and pharmacological inhibition of ERO1L with EN460 suppressed cell migration and invasion of PDAC. Furthermore, EN460 also suppressed hepatic metastasis of PDAC in vivo. Using shRNAs and EN460 to inhibit the ERO1L expression in Capan-2 and MiaPaca-2 led to the remarkable change of EMT-related protein Vimentin and E-cadherin, which indicated that EMT acted as a key pathway for ERO1L to promote invasion, dissemination, colonization, and growth of hepatic metastasis in PDAC. Conclusion Our findings uncover ERO1L contributes to hepatic metastasis in PDAC via epithelial-mesenchymal transition (EMT) process and indicate a promising therapeutic strategy for PDAC hepatic metastasis.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors
The results showed that Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) expression was significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) tissues comparing with paired normal pancreatic tissues using GSE16515 (Figure 1(a), n = 16, P = 0:002752), GSE15471 (Figure 1(a), n = 33, P = 4:513e − 06), and GSE102238 (Figure 1(a), n = 47, P = 6:582e − 07)
We mainly explored the role of ERO1L in hepatic metastasis of PDAC
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. Deciphering the molecular mechanisms of metastatic PDAC is urgently for exploring effective therapeutic targets. ERO1L is highly expressed in various types of human malignances, including but not limited to hepatocellular carcinoma (HCC), pancreatic cancer, gastric cancer, and breast cancer, which are associated with tumor progression and metastasis [7,8,9,10]. The mechanism of ERO1L on promoting metastasis of pancreatic ductal adenocarcinoma (PDAC) remains to be further explored. Using shRNAs and EN460 to inhibit the ERO1L expression in Capan-2 and MiaPaca-2 led to the remarkable change of EMT-related protein Vimentin and E-cadherin, which indicated that EMT acted as a key pathway for ERO1L to promote invasion, dissemination, colonization, and growth of hepatic metastasis in PDAC. Our findings uncover ERO1L contributes to hepatic metastasis in PDAC via epithelial-mesenchymal transition (EMT) process and indicate a promising therapeutic strategy for PDAC hepatic metastasis
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