JianYu Yang1,2, Yu Xu2, YanMiao Huo2, Li Cai3, Rong Hua2, JunFeng Zhang2, Zhong Chen1,4. 1. The First Affiliated Hospital of Soochow University, Suzhou, China. 2. Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 3. Kong Jiang Hospital of Yangpu District, Shanghai, China. 4. Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China.
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.
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.
Authors: Angela M Krebs; Julia Mitschke; María Lasierra Losada; Otto Schmalhofer; Melanie Boerries; Hauke Busch; Martin Boettcher; Dimitrios Mougiakakos; Wilfried Reichardt; Peter Bronsert; Valerie G Brunton; Christian Pilarsky; Thomas H Winkler; Simone Brabletz; Marc P Stemmler; Thomas Brabletz Journal: Nat Cell Biol Date: 2017-04-17 Impact factor: 28.824