Previous studies have shown distinct functions between c-jun NH2 terminal kinases (JNK) 1 and 2. Indeed, loss of JNK1 causes spontaneous intestinal tumor formation in mice (Tong et al, Am. J. Pathol, 2007; Hu et al, Carcinogenesis, 2008), but loss of JNK2 does not have any phenotype in intestine, although in vitro studies have shown that JNK2, like JNK1, interacts with and inhibits β-catenin signaling, in which GSK3β and proteasome pathway play a critical role (Hu et al, LoS One, 2009). To determine the role of genetic interaction between JNK2 and beta-catenin in intestinal tumorigenesis and to elucidate JNK2-mediated intestinal carcinogenesis, we crossed the JNK2−/−mouse with Apc+/− mice that carry inactivated Apc allele and develops intestinal tumor due to beta-catenin activation and nuclear accumulation. We found that the introduction of mutant JNK2 into Apc+/− did not increase intestinal tumorigenesis when the mice were fed a defined AIN-76A control diet. However, JNK2 reduction significantly increased animal body weight in the Apc+/−/JNK2+/− and Apc+/−/JNK2−/− mice. Interestingly, JNK2 reduction was synergistic with a Western-style high-risk diet (high fat and phosphate, low calcium and vitamin D)(WD) to accelerate intestinal tumorigenesis. Tumor number was significantly increased from 1.89 (AIN-76A diet) to 3.56 (WD) in the Apc+/−/JNK2+/− mice (P<0.01) and to 4.14 (WD) in the Apc+/−/JNK2−/− mice from 1.92 (AIN-76A diet) (P<0.01), even though there was a slight increase of tumor formation in JNK2 wild-type mice (Apc+/−/JNK2+/+) by such a diet (1.55 v.s. 2.0, p=0.4). Therefore, we concluded that JNK2 might have function in controlling fat metabolism, and that loss of JNK2 increases the risk of obesity, the latter synergists with high-fat diet to increase intestinal tumor susceptibility. This data strongly suggests the important role of JNK2 in intestinal carcinogenesis and the essential of dietary manipulation for cancer prevention in the population if their JNK2 is inactivated. The underlying mechanisms are under investigation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4163.