Abstract
Rapid progression and metastasis are the major causes of death in patients with pancreatic ductal adenocarcinoma (PDAC). ELK3, a member of the ternary complex factor (TCF), has been associated with the initiation and progression of various cancers. However, the role of ELK3 in PDAC is not yet fully understood. Online databases and immunohistochemistry were used to analyze the ELK3 levels in PDAC tissues. The function of ELK3 was confirmed by a series of in vivo and in vitro studies. Western blotting and immunofluorescence were used to detect the molecular mechanisms of PDAC. ChIP-qPCR was used to study the mechanism responsible for the elevation of ELK3 expression in PDAC. The ELK3 levels were higher in PDAC tissues than in adjacent normal tissues. Functionally, we demonstrated that ELK3 acted as an oncogene to promote PDAC tumorigenesis and metastasis. Further study suggested that ELK3 promoted PDAC cell migration and invasion by activating the Wnt/β-catenin pathway, and proved that ZEB1 could directly bind to the promoter of ELK3 to increase its transcription. Finally, both were associated with the patients’ clinicopathological features and worse overall survival. Conclusively, our findings enrich the role of ELK3 in PDAC, and provide potential avenues for exploring more effective biomarkers and therapeutic strategies for the treatment of PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains an intractable disease with a 5-year survival rate of 9%, which is the lowest among the different types of cancer (Siegel et al, 2020)
The Kaplan-Meier curve analyses revealed that elevated ELK3 level indicated poorer overall survival (OS) and relapse free survival (RFS) (P < 0.05) (Figure 1D)
In the lung metastasis model, we discovered that the number of metastatic nodules in mice injected with sh-ELK3/MIA PaCa-2 cells were less than in mice injected with sh-NC/MIA PaCa-2 cells (Figures 3G,H), while a higher number of metastatic nodules was observed in mice injected with ELK3/PANC-1 cells than in those injected with Ctrl/PANC-1 cells (Figures 3I,J)
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains an intractable disease with a 5-year survival rate of 9%, which is the lowest among the different types of cancer (Siegel et al, 2020). The function of ELK3 is capable of forming a ternary complex with serum response factor (SRF) to regulate gene expression (Nozaki et al, 1996; Li et al, 2000). Several studies have demonstrated that ELK3 is associated with the initiation and progression of various cancers. ELK3 suppression results in extensive changes in the expression profiles of breast cancer, decreases cell migration and metastasis during tumor progression (Kong et al, 2016). In squamous cell carcinoma (SCC), ELK3 knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCC (Yang et al, 2015). Increasing evidence has demonstrated the biological importance of ELK3, its role in PDAC and the potential molecular mechanisms have not been fully elucidated
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