Abstract
Trefoil factor 1 (TFF1) is a tumor suppressor gene that encodes a peptide belonging to the trefoil factor family of protease-resistant peptides. Although TFF1 expression is frequently lost in gastric carcinomas, the tumorigenic pathways this affects have not been determined. Here we show that Tff1-knockout mice exhibit age-dependent carcinogenic histological changes in the pyloric antrum of the gastric mucosa, progressing from gastritis to hyperplasia, low-grade dysplasia, high-grade dysplasia, and ultimately malignant adenocarcinoma. The histology and molecular signatures of gastric lesions in the Tff1-knockout mice were consistent with an inflammatory phenotype. In vivo, ex-vivo, and in vitro studies showed that TFF1 expression suppressed TNF-α-mediated NF-κB activation through the TNF receptor 1 (TNFR1)/IκB kinase (IKK) pathway. Consistent with these mouse data, human gastric tissue samples displayed a progressive decrease in TFF1 expression and an increase in NF-κB activation along the multi-step carcinogenesis cascade. Collectively, these results provide evidence that loss of TFF1 leads to activation of IKK complex-regulated NF-κB transcription factors and is an important event in shaping the NF-κB-mediated inflammatory response during the progression to gastric tumorigenesis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1753-1767 |
| Number of pages | 15 |
| Journal | Journal of Clinical Investigation |
| Volume | 121 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2 2011 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
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Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans. / Soutto, Mohammed; Belkhiri, Abbes; Piazuelo, M. Blanca; Schneider, Barbara G.; Peng, Dunfa; Jiang, Aixiang; Washington, M. Kay; Kokoye, Yasin; Crowe, Sheila E.; Zaika, Alexander; Correa, Pelayo; Peek, Richard M.; El-Rifai, Wael.
In: Journal of Clinical Investigation, Vol. 121, No. 5, 02.05.2011, p. 1753-1767.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans
AU - Soutto, Mohammed
AU - Belkhiri, Abbes
AU - Piazuelo, M. Blanca
AU - Schneider, Barbara G.
AU - Peng, Dunfa
AU - Jiang, Aixiang
AU - Washington, M. Kay
AU - Kokoye, Yasin
AU - Crowe, Sheila E.
AU - Zaika, Alexander
AU - Correa, Pelayo
AU - Peek, Richard M.
AU - El-Rifai, Wael
PY - 2011/5/2
Y1 - 2011/5/2
N2 - Trefoil factor 1 (TFF1) is a tumor suppressor gene that encodes a peptide belonging to the trefoil factor family of protease-resistant peptides. Although TFF1 expression is frequently lost in gastric carcinomas, the tumorigenic pathways this affects have not been determined. Here we show that Tff1-knockout mice exhibit age-dependent carcinogenic histological changes in the pyloric antrum of the gastric mucosa, progressing from gastritis to hyperplasia, low-grade dysplasia, high-grade dysplasia, and ultimately malignant adenocarcinoma. The histology and molecular signatures of gastric lesions in the Tff1-knockout mice were consistent with an inflammatory phenotype. In vivo, ex-vivo, and in vitro studies showed that TFF1 expression suppressed TNF-α-mediated NF-κB activation through the TNF receptor 1 (TNFR1)/IκB kinase (IKK) pathway. Consistent with these mouse data, human gastric tissue samples displayed a progressive decrease in TFF1 expression and an increase in NF-κB activation along the multi-step carcinogenesis cascade. Collectively, these results provide evidence that loss of TFF1 leads to activation of IKK complex-regulated NF-κB transcription factors and is an important event in shaping the NF-κB-mediated inflammatory response during the progression to gastric tumorigenesis.
AB - Trefoil factor 1 (TFF1) is a tumor suppressor gene that encodes a peptide belonging to the trefoil factor family of protease-resistant peptides. Although TFF1 expression is frequently lost in gastric carcinomas, the tumorigenic pathways this affects have not been determined. Here we show that Tff1-knockout mice exhibit age-dependent carcinogenic histological changes in the pyloric antrum of the gastric mucosa, progressing from gastritis to hyperplasia, low-grade dysplasia, high-grade dysplasia, and ultimately malignant adenocarcinoma. The histology and molecular signatures of gastric lesions in the Tff1-knockout mice were consistent with an inflammatory phenotype. In vivo, ex-vivo, and in vitro studies showed that TFF1 expression suppressed TNF-α-mediated NF-κB activation through the TNF receptor 1 (TNFR1)/IκB kinase (IKK) pathway. Consistent with these mouse data, human gastric tissue samples displayed a progressive decrease in TFF1 expression and an increase in NF-κB activation along the multi-step carcinogenesis cascade. Collectively, these results provide evidence that loss of TFF1 leads to activation of IKK complex-regulated NF-κB transcription factors and is an important event in shaping the NF-κB-mediated inflammatory response during the progression to gastric tumorigenesis.
UR - http://www.scopus.com/inward/record.url?scp=79955509042&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955509042&partnerID=8YFLogxK
U2 - 10.1172/JCI43922
DO - 10.1172/JCI43922
M3 - Article
C2 - 21490402
AN - SCOPUS:79955509042
VL - 121
SP - 1753
EP - 1767
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 5
ER -