TFF1 activates p53 through down-regulation of miR-504 in gastric cancer

The expression of TFF1 is frequently down-regulated in human gastric cancer whereas its knockout leads to the development of gastric adenomas and carcinomas in mouse models. The molecular mechanisms underlying the TFF1 tumor suppressor functions remain unclear. In this study, we demonstrate, using c...

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Bibliographic Details
Published in:Oncotarget 2014-07, Vol.5 (14), p.5663-5673
Main Authors: Soutto, Mohammed, Chen, Zheng, Saleh, Mohamed A, Katsha, Ahmed, Zhu, Shoumin, Zaika, Alexander, Belkhiri, Abbes, El-Rifai, Wael
Format: Article
Language:English
Subjects:
Animals
Apoptosis - physiology
Cell Line, Tumor
Cell Proliferation - physiology
Disease Models, Animal
Down-Regulation
Female
Humans
Mice
Mice, Nude
MicroRNAs - genetics
MicroRNAs - metabolism
Research Paper
Stomach Neoplasms - genetics
Stomach Neoplasms - metabolism
Trefoil Factor-1
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Xenograft Model Antitumor Assays
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Summary:The expression of TFF1 is frequently down-regulated in human gastric cancer whereas its knockout leads to the development of gastric adenomas and carcinomas in mouse models. The molecular mechanisms underlying the TFF1 tumor suppressor functions remain unclear. In this study, we demonstrate, using colony formation assay and Annexin V staining, that reconstitution of TFF1 expression in gastric cancer cell models suppresses cell growth and promotes cell death. Furthermore, using a tumor xenograft mouse model of gastric cancer, we demonstrated that reconstitution of TFF1 suppresses tumor growth in vivo. The results from PG13-luciferase reporter assay and Western blot analysis indicated that TFF1 promotes the expression and transcription activity of p53 protein. Further analysis using cycloheximide-based protein assay and quantitative real-time PCR data suggested that TFF1 does not interfere with p53 mRNA levels or protein stability. Alternatively, we found that the reconstitution of TFF1 down-regulates miR-504, a negative regulator of p53. Western blot analysis data demonstrated that miR-504 abrogates TFF1-induced p53 protein expression and activity. In conclusion, the in vitro and in vivo data demonstrate, for the first time, a novel mechanism by which the tumor suppressor functions of TFF1 involve activation of p53 through down-regulation of miR-504.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.2156