Targeted Intervention of eIF4A1 Promotes EMT and Metastasis of Pancreatic Cancer Cells through c-MYC/miR-9 Signaling

Abstract Background: Due to the lack of effective interference options, early metastasis remains a major cause of pancreatic ductal adenocarcinoma (PDAC) recurrence and mortality. However, the molecular mechanism of early metastasis is largely unknown. We characterize the function of eukaryotic translation initiation factors (eIFs) in Pancreatic cancer cell epithelial mesenchymal-transition (EMT) and metastasis, to investigate whether it is effective to inhibit EMT and metastasis by joint interference of eIFs and downstream c-MYC. Methods: We used the data of The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) to analyze the expression level of eIF4A1 in PDAC tissues, and further validated in a microarray containing 53 PDAC samples. Expression regulation and pharmacological inhibition of eIF4A1/c-MYC was performed to determine their role in migration, invasion, and metastasis in pancreatic cancer cells in vitro and in vivo.Results: Elevated expression of eIF4A1 was positively correlated with lymph node infiltration, tumor size, and indicated a poor prognosis. eIF4A1 decreased E-cadherin expression through c-MYC/miR-9 axis. Ablation of eIF4A1 and c-MYC decreased the EMT and metastasis capabilities of pancreatic cancer cells. Upregulation of eIF4A1 could attenuate the inhibition of EMT and metastasis induced by c-MYC downregulation. Single-use of eIF4A1 inhibitor Rocaglamide (RocA) or c-MYC inhibitor Mycro3 and joint intervention all significantly the EMT level of pancreatic cancer cells in vitro. However, the efficiency and safety of RocA single-use were not inferior to joint use in vivo. Conclusion: The results demonstrated that overexpression of eIF4A1 downregulated E-cadherin through c-MYC/miR-9 axis, which promoted EMT and metastasis of pancreatic cancer cells. Despite the potential loop between eIF4A1 and c-MYC existing, RocA single strategy was a promising therapy for the inhibition of eIF4A1 induced PDAC metastasis.