Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia
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Published on: November 9, 2018
Seung Joon Baek1, Ryuji Okazaki, Seong-Ho Lee
1Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, USA.
Background & Aims:
The nonsteroidal anti-inflammatory drug-activated gene (NAG-1) was identified as a proapoptotic, antitumorigenic protein in vitro, induced by many antitumorigenic and chemopreventive drugs including cyclooxygenase inhibitors. However, its antitumorigenic activity has not been elucidated in vivo.
Methods:
Transgenic mice were generated that ubiquitously overexpress human NAG-1 under the control of a chicken beta-actin promoter (CAG). The NAG-1 transgenic mice (NAG-(Tg+)) were characterized, and then the antitumorigenic activity was evaluated with 2 colorectal carcinogenesis models: chemical induction with azoxymethane and genetic induction using the Apc(Min+) mutation.
Results:
NAG-(Tg+) showed no apparent phenotype other than a reduction in body weight, particularly in males. To examine whether NAG-1 expression would suppress intestinal tumorigenesis, the NAG-(Tg+) mice were treated with the colorectal carcinogen azoxymethane. NAG-(Tg+) mice developed 50% fewer aberrant crypt foci and no tumors, in comparison with nontransgenic littermates. This result demonstrates that expression of this human protein in vivo can suppress chemically induced carcinogenesis in the colon. The NAG-(Tg+) mice were also crossed with Apc(Min+) mice to determine the effect of the transgene on intestinal polyp formation. NAG-(Tg+) mice heterozygous for the Apc(Min+) mutation had a significantly reduced polyp load (60%) compared with nontransgenic Apc(Min+) littermates.
Conclusions:
Our results support NAG-1 as an important regulator of intestinal adenoma growth in vivo and suggest that NAG-1 may act as a tumor suppressor gene.
Insights
The nonsteroidal anti-inflammatory drug-activated gene (NAG-1) suppresses intestinal tumor growth in vivo. Overexpressing NAG-1 in mice reduced chemically induced tumors and polyps, suggesting it acts as a tumor suppressor.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is a proapoptotic and antitumorigenic protein identified in vitro.
- NAG-1 is induced by various chemopreventive drugs, including cyclooxygenase inhibitors.
- The in vivo antitumorigenic activity of NAG-1 remains largely unelucidated.
Purpose of the Study:
- To investigate the in vivo antitumorigenic activity of NAG-1.
- To evaluate the potential of NAG-1 as a tumor suppressor gene in the context of colorectal cancer.
Main Methods:
- Generation of transgenic mice overexpressing human NAG-1 (NAG-(Tg+)) under the CAG promoter.
- Evaluation of antitumorigenic activity using two colorectal carcinogenesis models: azoxymethane induction and Apc(Min+) mutation.
- Assessment of aberrant crypt foci, tumor formation, and polyp load in NAG-(Tg+) mice compared to controls.
Main Results:
- NAG-(Tg+) mice exhibited a slight reduction in body weight, particularly males, but no other apparent phenotype.
- Azoxymethane-treated NAG-(Tg+) mice showed a 50% reduction in aberrant crypt foci and no tumors compared to nontransgenic littermates.
- NAG-(Tg+) mice crossed with Apc(Min+) mice displayed a 60% reduction in intestinal polyp load.
Conclusions:
- NAG-1 plays a significant role in regulating intestinal adenoma growth in vivo.
- The findings support NAG-1's function as a tumor suppressor gene.
- NAG-1 overexpression demonstrates potential for suppressing colorectal carcinogenesis.
