title: TFF1 activates p53 through down-regulation of miR-504 in gastric cancer.
abstract: 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.
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA. Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Soutto
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Saleh
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Katsha
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Shoumin
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zaika
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Abbes
authors.initials: A
authors.lastname: Belkhiri
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA. Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism*; D000071163:Trefoil Factor-1; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C550379:MIRN504 microRNA, human; D035683:MicroRNAs; C051838:TFF1 protein, human; C495901:TP53 protein, human; D000071163:Trefoil Factor-1; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins