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Trefoil factor family (TFF) peptides have been shown to play a pivotal role in oncogenic transformation, tumorigenesis and metastasis by changing cell proliferation, apoptosis, migration and invasion behavior of various cancer cell lines. In the study presented, we investigated the effect ofTFF1overexpression on cell growth, viability, migration and tumorigenicity of different retinoblastoma (RB) cell lines. TransientTFF1overexpression significantly increases RB cell apoptosis levels. Stable, lentiviralTFF1overexpression likewise decreases RB cell viability, proliferation and growth and significantly increases apoptosis as revealed by WST-1 assays, BrdU and DAPI cell counts.TFF1-induced apoptosis is executed via cleaved caspase-3 activation as revealed by caspase blockage experiments and caspase-3 immunocytochemistry. Results from pG13-luciferase reporter assays and Western blot analyses indicate thatTFF1-induced apoptosis is mediated through transcriptional activity of p53 with concurrently downregulated miR-18a expression.In ovochicken chorioallantoic membrane (CAM) assays revealed thatTFF1overexpression significantly decreases the size of tumors forming from Y79 and RB355 cells and reduces the migration potential of RB355 cells. Differentially expressed genes and pathways involved in cancer progression were identified afterTFF1overexpression in Y79 cells by gene expression array analysis, underlining the effects on reduced tumorigenicity.TFF1knockdown in RBL30 cells revealed caspase-3/7-independent apoptosis induction, but no changes on cell proliferation level. In summary, thein vitroandin vivodata demonstrate for the first time a tumor suppressor function ofTFF1in RB cells which is at least partly mediated by p53 activation and miR-18a downregulation.