TFF1 activates p53 through down-regulation of miR-504 in gastric cancer
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Mohammed Soutto1,2, Zheng Chen2, Mohamed A. Saleh3,5, Ahmed Katsha2, Shoumin Zhu2, Alexander Zaika2, Abbes Belkhiri2 and Wael El-Rifai1,2,4
1 Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
2 Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
3 Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
4 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
5 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
Wael El-Rifai, email:
Keywords: TFF1, p53, gastric cancer, miR-504, apoptosis
Received: May 21, 2014 Accepted: June 30, 2014 Published: July 1, 2014
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 the 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.
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