Inflammatory bowel disease (IBD) increases the risk of colon cancer. The etiologies of inflammatory bowel diseases include genetic background and western life style that impair the microbial flora in the gut, such as diets high in fat and low in fiber and calcium. These factors combine to compromise the innate immunity of the gut and to increase the susceptibility to bacterial infections and chronic inflammation. To determine the cellular events and signaling pathways that may be involved with response to luminal factors that increase susceptibility to malignant transformation, we have employed the model of transmissible murine colonic hyperplasia (TMCH) induced by the gram-negative bacterium citrobacter rodentium (CR). The infected mice develop a moderate inflammatory response restricted to the distal colon and extreme hyperplasia of the colonic crypts. These responses are generally self-limited, but clearly increase the susceptibility to develop colon cancer in either carcinogen-treated or genetically-altered (i.e., mutation in the tumor-suppressing gene, Apc) mice. A potential explanation for these findings is provided by recent studies, which have shown that TMCH is associated with an early and sustained elevation of two powerful modifiers of epithelial proliferation, (-catenin and NF-(B. By using either fiber-rich (pectin) or high calcium diets, we found that both diets inhibited the hyperplasia. However, the pectin-rich diet diminished the activities of 2-catenin and NF-(B, but the calcium-rich diet did not affect these two growth-promoting and anti-apoptotic pathways. This led us to conclude that high calcium diet acted by inhibiting a third, powerful growth-promoting pathway, which was independent of NF-(B and (-catenin. Preliminary assessment of several gene products associated with response to calcium in the gut has revealed a dramatic upregulation of the calcium channel TRPV6 in the infected colon and a significant repression of this gene in the colon of infected mice given 1% dietary calcium. Since elevated expression of TRPV6 was found in other malignancies, including colon cancer, we hypothesized that disrupted calcium signaling caused by over expression of TRPV6 contributes to CR-induced colonic hyperplasia and this abnormal cellular response can be prevented by downregulation of TRPV6 with dietary calcium. To test this hypothesis we propose the following aims: 1) WT and TRPV6-ablated (KO) mice will be used to determine the contribution of the TRPV6 gene product to the hyperplasia and the inflammation in TMCH;2) these mice will be also used to determine if inhibition of TMCH by high calcium diet is dependent on TRPV6 expression. These studies should provide an insight into the mechanisms whereby dietary calcium prevents pre-neoplastic hyperplasia in the colon and might establish the basis for dietary recommendations that reduce the risk of colon cancer.
This study will focus on the mechanisms by which dietary calcium attenuates abnormal cell growth in the colon. Such abnormal cell growth occurs after bacterial infections and can increase susceptibility to develop colon cancer. By identifying the target genes for the protective actions of calcium we can design drugs that block their expression/activities and reverse damages that develop during life-long exposure of the colon to calcium-deficient diets.
| Peleg, Sara; Sellin, Joseph H; Wang, Yu et al. (2010) Suppression of aberrant transient receptor potential cation channel, subfamily V, member 6 expression in hyperproliferative colonic crypts by dietary calcium. Am J Physiol Gastrointest Liver Physiol 299:G593-601 |
| Chandrakesan, Parthasarathy; Ahmed, Ishfaq; Anwar, Tariq et al. (2010) Novel changes in NF-{kappa}B activity during progression and regression phases of hyperplasia: role of MEK, ERK, and p38. J Biol Chem 285:33485-98 |
