Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis

Mohammed Soutto, Judith Romero-Gallo, Uma Krishna, M. Blanca Piazuelo, M. Kay Washington, Abbes Belkhiri, Richard M. Peek, Wael El-Rifai

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Using in vitro and in vivo models, we investigated the role of TFF1 in suppressing H. pylori-mediated activation of oncogenic β-catenin in gastric tumorigenesis. A reconstitution of TFF1 expression in gastric cancer cells decreased H. pylori-induced β-catenin nuclear translocation, as compared to control (p < 0.001). These cells exhibited significantly lower β-catenin transcriptional activity, measured by pTopFlash reporter, and induction of its target genes (CCND1 and c-MYC), as compared to control. Because of the role of AKT in regulating β-catenin, we performed Western blot analysis and demonstrated that TFF1 reconstitution abrogates H. pylori-induced p-AKT (Ser473), p-β-catenin (Ser552), c-MYC, and CCND1 protein levels. For in vivo validation, we utilized the Tff1-KO gastric neoplasm mouse model. Following infection with PMSS1 H. pylori strain, we detected an increase in the nuclear staining for β-catenin and Ki-67 with a significant induction in the levels of Ccnd1 and c-Myc in the stomach of the Tff1-KO, as compared to Tff1-WT mice (p < 0.05). Only 10% of uninfected Tff1-KO mice, as opposed to one-third of H. pylori-infected Tff1-KO mice, developed invasive adenocarcinoma (p = 0.03). These findings suggest that loss of TFF1 could be a critical step in promoting the H. pylori-mediated oncogenic activation of β-catenin and gastric tumorigenesis.

Original languageEnglish (US)
Pages (from-to)17911-17922
Number of pages12
JournalOncotarget
Volume6
Issue number20
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Catenins
Helicobacter pylori
Stomach
Carcinogenesis
Stomach Neoplasms
Cyclin D1
Adenocarcinoma
Western Blotting
Staining and Labeling
Infection
Genes

Keywords

  • Gastric cancer
  • Helicobacter pylori
  • TFF1
  • β-catenin

ASJC Scopus subject areas

  • Oncology

Cite this

Soutto, M., Romero-Gallo, J., Krishna, U., Blanca Piazuelo, M., Kay Washington, M., Belkhiri, A., ... El-Rifai, W. (2015). Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis. Oncotarget, 6(20), 17911-17922. https://doi.org/10.18632/oncotarget.3772

Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis. / Soutto, Mohammed; Romero-Gallo, Judith; Krishna, Uma; Blanca Piazuelo, M.; Kay Washington, M.; Belkhiri, Abbes; Peek, Richard M.; El-Rifai, Wael.

In: Oncotarget, Vol. 6, No. 20, 01.01.2015, p. 17911-17922.

Research output: Contribution to journalArticle

Soutto, M, Romero-Gallo, J, Krishna, U, Blanca Piazuelo, M, Kay Washington, M, Belkhiri, A, Peek, RM & El-Rifai, W 2015, 'Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis', Oncotarget, vol. 6, no. 20, pp. 17911-17922. https://doi.org/10.18632/oncotarget.3772
Soutto M, Romero-Gallo J, Krishna U, Blanca Piazuelo M, Kay Washington M, Belkhiri A et al. Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis. Oncotarget. 2015 Jan 1;6(20):17911-17922. https://doi.org/10.18632/oncotarget.3772
Soutto, Mohammed ; Romero-Gallo, Judith ; Krishna, Uma ; Blanca Piazuelo, M. ; Kay Washington, M. ; Belkhiri, Abbes ; Peek, Richard M. ; El-Rifai, Wael. / Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis. In: Oncotarget. 2015 ; Vol. 6, No. 20. pp. 17911-17922.
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