My lab is interested in the signaling pathways involved in the development of colon cancer. Unlike diseases that are caused by mutation of a particular gene, cancer is a disease that can involve many different genes. In the process of becoming cancerous, a normal cell acquires a mutation that makes it more prone to further mutations. Once it acquires several mutations, the cell becomes more cancerous and can eventually form a local tumor in the same tissue or a metastatic tumor that travels to other organs in the body.
Our research focuses on identifying cancer genes that interact with environmental risk factors, such as fats in the diet, to cause cancer.
Environmental risk factors play a major role in cancer. In fact, it is estimated that more than 50 percent of cancers are due to exposure to environmental risk factors. For example, more than 30 percent of all cancer and 95 percent of lung cancers can be prevented by eliminating tobacco use. In addition, diet and other lifestyle factors contribute to about 30 percent of cancers, although the mechanism by which these environmental factors interact with genes to cause cancer is not as clear.
We are investigating a gene, PKC iota, which appears to be regulated by fats in the diet that are known to cause cancer. In addition, we have shown that PKC iota interacts with K-ras, a gene known to play a role in causing colon cancer. For that reason, we are investigating the role of PKC iota in colon cancer.
We use a combination of new technologies in tissue cell cultures and animal colon cancer models to learn how PKC iota transforms normal cells into cancer cells. What we learn will be used to develop drugs that inhibit the PKC iota gene, to create new models to test cancer-fighting drugs and to identify patients who are likely to respond to targeted cancer therapy.
Read on for a more technical discussion:
Colon cancer results from progressive loss of regulation of the normal growth inhibitory, differentiation and apoptotic signals in colonic epithelial cells. Our long-term goal is to understand the role of protein kinase C (PKC) isozymes in colonic epithelial cell biology and colon carcinogenesis. Using an in vivo transgenic mouse model system, we have recently demonstrated a direct role for PKCβII in colonic epithelial cell proliferation and colon carcinogenesis. We are currently investigating the interaction of dietary fat and colonic PKCβII function in susceptibility to colon carcinogenesis.
Several lines of evidence suggest that the atypical PKC iota isoform (CKPi) also plays an important promotive role in colon carcinogenesis.
Taken together these data indicate that PKCi plays a key role in colon carcinogenesis by enhancing cell survival. We hypothesize that PKCi protects colonic epithelial cells against apoptosis and that elevated PKCi in the colonic epithelium will result in an increased susceptibility to colon carcinogenesis. We have generated transgenic mice that express constitutively active (ca) or dominant-negative (dn) mutant forms of PKCi in the colonic epithelium.
Future studies will investigate the role of PKCi in colonic epithelial cell homeostasis and susceptibility to colon carcinogenesis by further characterizing our caPKCi and dnPKCi transgenic mice. In addition, we will assess the role of PKCi in mediating the effects of K-ras on colonic epithelial cell homeostasis, colon carcinogenesis and NF-κB signaling in-vivo.
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