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.

中文翻译：

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ERO1L 通过激活胰腺癌的上皮间质转化 (EMT) 促进肝转移

背景。内质网氧化还原酶 1 α (ERO1L) 作为人类恶性肿瘤中肿瘤生长的效应物。然而，ERO1L促进胰腺导管腺癌（PDAC）转移的机制仍有待进一步探索。方法。对公共数据库和大规模转移性 PDAC 测序进行了生物信息学分析，以确定 ERO1L 在 PDAC 中的表达谱和预后价值。通过细胞生物学、分子和生化方法，在体外和体内分析了 ERO1L 对 PDAC 转移的影响。结果. PDAC 肝转移组织中的 ERO1L 高表达并与无病生存 (DFS) 相关。用 EN460 对 ERO1L 进行基因沉默和药理学抑制抑制了 PDAC 的细胞迁移和侵袭。此外，EN460 还在体内抑制 PDAC 的肝转移。利用shRNAs和EN460抑制Capan-2和MiaPaca-2中ERO1L的表达，导致EMT相关蛋白Vimentin和E-cadherin发生显着变化，表明EMT是ERO1L促进侵袭、传播、 PDAC中的定植和肝转移的生长。结论。我们的研究结果揭示了 ERO1L 通过上皮 - 间质转化 (EMT) 过程促进 PDAC 肝转移，并表明 PDAC 肝转移的有希望的治疗策略。