Journal Article

Loss of JNK2 increases intestinal tumor susceptibility in <i>Apc1638+/−</i> mice with dietary modulation

Xiuli Bi, Nicole M. Pohl, Zhinan Yin and Wancai Yang

in Carcinogenesis

Volume 32, issue 4, pages 584-588
Published in print April 2011 | ISSN: 0143-3334
Published online December 2010 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgq275
Loss of JNK2 increases intestinal tumor susceptibility in Apc1638+/− mice with dietary modulation

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A recent study has shown that c-Jun NH2-terminal kinases (JNKs) 2 interacts with and inhibits β-catenin signaling in vitro. To determine the role of genetic interaction between JNK2 and β-catenin in vivo and to elucidate JNK2-mediated intestinal carcinogenesis, we crossed the JNK2−/− mice with Apc1638+/− mice that carry inactivated Apc allele and develop intestinal tumor due to β-catenin activation. We found that the introduction of mutant JNK2 into Apc1638+/− mice did not increase intestinal tumorigenesis when the mice were fed a defined AIN-76A control diet. However, loss of JNK2 significantly increased animal body weight in the Apc/JNK2+/− and Apc/JNK2−/− mice. Surprisingly, JNK2 loss was synergistic with a Western-style high-risk diet (high fat and phosphate and low calcium and vitamin D) to accelerate intestinal tumorigenesis. Tumor number increased to 3.56 from 1.89 (on AIN-76A diet) in the Apc/JNK2+/− mice (P < 0.01) and increased to 4.14 from 1.92 (on AIN-76A diet) in the Apc/JNK2−/− mice (P < 0.01) although there was a slight increase of tumor formation in Apc/JNK2+/+ mice. Intestinal tumorigenesis in Apc/JNK2 double-mutant mice with high-risk diet modulation was associated with β-catenin signaling, peroxisome proliferator–activated receptor-γ and inflammation pathway. Collectively, we concluded that JNK2 may function in controlling fat metabolism and loss of JNK2 increases the risk of obesity, the latter synergizes with high-fat diet to increase intestinal tumor susceptibility. This data strongly suggests the importance of JNK2 in intestinal carcinogenesis and the importance of dietary manipulation for cancer prevention in the population whose JNK2 is inactivated.

Journal Article.  3366 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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