Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis

Mohammed Soutto, Dunfa Peng, Ahmed Katsha, Zheng Chen, Maria Blanca Piazuelo, Mary Kay Washington, Abbes Belkhiri, Pelayo Correa, Wael El-Rifai

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Objective In this study, we investigated the role of Trefoil factor 1 (TFF1) in regulating cell proliferation and tumour development through β-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 β-catenin signalling pathway. Results: Nuclear localisation of β-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 β-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 β-catenin with downregulation of c-MYC and CCND1 mRNA. Analysis of signalling molecules upstream of β-catenin revealed a decrease in phosphorylated glycogen synthase kinase 3β (p-GSK3β) (Ser9) and p-AKT (Ser473) protein levels following the reconstitution of TFF1 expression; this was consistent with the increase of p-β-catenin (Ser33/37/Thr41) and decrease of p-β-catenin (Ser552). This TFF1-induced reduction in phosphorylation of GSK3β, 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 β-catenin in stages of human gastric tumorigenesis. Conclusions: Our data indicate that loss of TFF1 promotes β-catenin activation and gastric tumorigenesis through regulation of PP2A, a major regulator of AKT-GSK3β signalling.

Original languageEnglish (US)
Pages (from-to)1028-1039
Number of pages12
JournalGut
Volume64
Issue number7
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

Fingerprint

Catenins
Stomach
Carcinogenesis
Cell Proliferation
Protein Phosphatase 2
Knockout Mice
Trefoil Factor-1
TCF Transcription Factors
Glycogen Synthase Kinase 3
Okadaic Acid
myc Genes
Conditioned Culture Medium
Luciferases
Phosphoric Monoester Hydrolases
Stomach Neoplasms
Up-Regulation
Down-Regulation
Immunohistochemistry
Phosphorylation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis. / Soutto, Mohammed; Peng, Dunfa; Katsha, Ahmed; Chen, Zheng; Piazuelo, Maria Blanca; Washington, Mary Kay; Belkhiri, Abbes; Correa, Pelayo; El-Rifai, Wael.

In: Gut, Vol. 64, No. 7, 01.07.2015, p. 1028-1039.

Research output: Contribution to journalArticle

Soutto, M, Peng, D, Katsha, A, Chen, Z, Piazuelo, MB, Washington, MK, Belkhiri, A, Correa, P & El-Rifai, W 2015, 'Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis', Gut, vol. 64, no. 7, pp. 1028-1039. https://doi.org/10.1136/gutjnl-2014-307191
Soutto, Mohammed ; Peng, Dunfa ; Katsha, Ahmed ; Chen, Zheng ; Piazuelo, Maria Blanca ; Washington, Mary Kay ; Belkhiri, Abbes ; Correa, Pelayo ; El-Rifai, Wael. / Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis. In: Gut. 2015 ; Vol. 64, No. 7. pp. 1028-1039.
@article{e5e162d265ea49569940a580e6db4d8a,
title = "Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis",
abstract = "Objective In this study, we investigated the role of Trefoil factor 1 (TFF1) in regulating cell proliferation and tumour development through β-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 β-catenin signalling pathway. Results: Nuclear localisation of β-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 β-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 β-catenin with downregulation of c-MYC and CCND1 mRNA. Analysis of signalling molecules upstream of β-catenin revealed a decrease in phosphorylated glycogen synthase kinase 3β (p-GSK3β) (Ser9) and p-AKT (Ser473) protein levels following the reconstitution of TFF1 expression; this was consistent with the increase of p-β-catenin (Ser33/37/Thr41) and decrease of p-β-catenin (Ser552). This TFF1-induced reduction in phosphorylation of GSK3β, 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 β-catenin in stages of human gastric tumorigenesis. Conclusions: Our data indicate that loss of TFF1 promotes β-catenin activation and gastric tumorigenesis through regulation of PP2A, a major regulator of AKT-GSK3β signalling.",
author = "Mohammed Soutto and Dunfa Peng and Ahmed Katsha and Zheng Chen and Piazuelo, {Maria Blanca} and Washington, {Mary Kay} and Abbes Belkhiri and Pelayo Correa and Wael El-Rifai",
year = "2015",
month = "7",
day = "1",
doi = "10.1136/gutjnl-2014-307191",
language = "English (US)",
volume = "64",
pages = "1028--1039",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",
number = "7",

}

TY - JOUR

T1 - Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis

AU - Soutto, Mohammed

AU - Peng, Dunfa

AU - Katsha, Ahmed

AU - Chen, Zheng

AU - Piazuelo, Maria Blanca

AU - Washington, Mary Kay

AU - Belkhiri, Abbes

AU - Correa, Pelayo

AU - El-Rifai, Wael

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Objective In this study, we investigated the role of Trefoil factor 1 (TFF1) in regulating cell proliferation and tumour development through β-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 β-catenin signalling pathway. Results: Nuclear localisation of β-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 β-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 β-catenin with downregulation of c-MYC and CCND1 mRNA. Analysis of signalling molecules upstream of β-catenin revealed a decrease in phosphorylated glycogen synthase kinase 3β (p-GSK3β) (Ser9) and p-AKT (Ser473) protein levels following the reconstitution of TFF1 expression; this was consistent with the increase of p-β-catenin (Ser33/37/Thr41) and decrease of p-β-catenin (Ser552). This TFF1-induced reduction in phosphorylation of GSK3β, 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 β-catenin in stages of human gastric tumorigenesis. Conclusions: Our data indicate that loss of TFF1 promotes β-catenin activation and gastric tumorigenesis through regulation of PP2A, a major regulator of AKT-GSK3β signalling.

AB - Objective In this study, we investigated the role of Trefoil factor 1 (TFF1) in regulating cell proliferation and tumour development through β-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 β-catenin signalling pathway. Results: Nuclear localisation of β-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 β-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 β-catenin with downregulation of c-MYC and CCND1 mRNA. Analysis of signalling molecules upstream of β-catenin revealed a decrease in phosphorylated glycogen synthase kinase 3β (p-GSK3β) (Ser9) and p-AKT (Ser473) protein levels following the reconstitution of TFF1 expression; this was consistent with the increase of p-β-catenin (Ser33/37/Thr41) and decrease of p-β-catenin (Ser552). This TFF1-induced reduction in phosphorylation of GSK3β, 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 β-catenin in stages of human gastric tumorigenesis. Conclusions: Our data indicate that loss of TFF1 promotes β-catenin activation and gastric tumorigenesis through regulation of PP2A, a major regulator of AKT-GSK3β signalling.

UR - http://www.scopus.com/inward/record.url?scp=84934983232&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84934983232&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2014-307191

DO - 10.1136/gutjnl-2014-307191

M3 - Article

C2 - 25107557

AN - SCOPUS:84934983232

VL - 64

SP - 1028

EP - 1039

JO - Gut

JF - Gut

SN - 0017-5749

IS - 7

ER -