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摘要
Objective In this study, we investigated the role of Trefoil factor 1 (TFF1) in regulating cell proliferation and tumour development through beta-catenin signalling using in vivo and in vitro models of gastric tumorigenesis. Design Tff1-knockout (Tff1-KO) mice, immunohistochemistry, luciferase reporter, qRT-PCR, immunoblot, and phosphatase assays were used to examine the role of TFF1 on beta-catenin signalling pathway. Results Nuclear localisation of beta-catenin with transcriptional upregulation of its target genes, c-Myc and Ccnd1, was detected in hyperplastic tissue at an early age of 4-6 weeks and maintained during all stages of gastric tumorigenesis in the Tff1-KO mice. The reconstitution of TFF1 or TFF1 conditioned media significantly inhibited the beta-catenin/T-cell factor (TCF) transcription activity in MKN28 gastric cancer cells. In agreement with these results, we detected a reduction in the levels of nuclear beta-catenin with downregulation of c-MYC and CCND1 mRNA. Analysis of signalling molecules upstream of beta-catenin revealed a decrease in phosphorylated glycogen synthase kinase 3 beta (p-GSK3 beta) (Ser9) and p-AKT (Ser473) protein levels following the reconstitution of TFF1 expression; this was consistent with the increase of p-beta-catenin (Ser33/37/Thr41) and decrease of p-beta-catenin (Ser552). This TFF1-induced reduction in phosphorylation of GSK3 beta, and AKT was dependent on protein phosphatase 2A (PP2A) activity. The treatment with okadaic acid or knockdown of PP2A abrogated these effects. Consistent with the mouse data, we observed loss of TFF1 and an increase in nuclear localisation of beta-catenin in stages of human gastric tumorigenesis. Conclusions Our data indicate that loss of TFF1 promotes beta-catenin activation and gastric tumorigenesis through regulation of PP2A, a major regulator of AKT-GSK3 beta signalling.
- 出版日期2015-7
