Purpose: Our previous work identified leucine zipper transcription factor-like 1 (LZTFL1) as a novel tumor suppressor gene, with its expression correlated with survival outcome in gastric cancer (GC) patients. This study focuses on the role of LZTFL1 in GC aggression and metastasis as well as its underlying molecular mechanisms.
Method: LZTFL1 immunohistochemical (IHC) staining on 311 paired normal/cancer tissue arrays were used to reconfirm the clinical significance of LZTFL1 expression. Transwell chamber assays were used to determine migration and invasive ability of GC cells. Gelatin zymography was employed to investigate the matrix metalloproteinases (MMPs) activity in tumor cells. Co-immunoprecipitation and Duolink in situ proximity ligation assay were used to analyze the interaction between LZTFL1 and β-catenin and the cellular localization of the interaction.
Result: IHC results indicated that patients with high LZTFL1 expression had a longer overall survival time (58 months, 95 % CI 28-128 months) than patients with low LZTFL1 expression (27 months, 95 % CI 23-35 months; p < 0.01). The expression level of LZTFL1 is associated with the degree of cell differentiation. LZTFL1 is necessary and sufficient to inhibit the expression of molecular markers associated with epithelial-mesenchymal transition (EMT) and cellular phenotypes associated with tumor cell EMT including the migration, invasion, and the expression and activities of MMPs of tumor cells. LZTFL1 binds β-catenin in the cytoplasm of the cell and inhibited its nuclear translocation.
Conclusion: LZTFL1 suppresses GC cell EMT by inhibiting β-catenin nuclear translocation. Re-expression of LZTFL1 in GC cells may be a potential therapeutic means to prevent GC metastasis.