A novel molecular mechanism to explain the association between obesity and increased colon inflammation risk which is a major risk factor in colorectal cancer. The study was conducted by doctoral candidates Wiecang Wang and Jianan Zhang, with their advisor Guodong Zhang in the department of food science at the University of Massachusetts Amherst.
The research team, which includes scientists at the University of California Davis note that a few sEH inhibitors, known to be a factor in other inflammatory diseases but not colon cancer before, are now in human clinical trials. Senior author Zhang says, "In our mouse studies, obesity-induced colon inflammation can be eliminated by inhibiting sEH. So we discovered a new therapeutic target for a very important disease." Because sEH inhibitors are already being explored as a treatment for other diseases such as pain and hypertension, he notes, medical researchers using it would not need to reinvent a whole new approach. "We hope it will be a promising treatment in humans, but mice and humans are very different," Zhang cautions. Details appear in an early online issue of Proceedings of the National Academy of Sciences.
As the authors point out, more than one-third, or 34.9 percent, of adults in the United States are obese, and obese individuals have a 30-60 percent higher risk of developing colorectal cancer, the third most common and the second leading cause of cancer-related death in the nation. Colon inflammation is an early warning sign of this cancer, and the new research shows why and how obesity increases risk. In this study, the investigators used a liquid chromatography tandem mass spectrometry (LC-MS/MS)-based metabolomics approach to analyze the profiles of signaling lipids in the colon of groups of lean and obese mice. This allowed them to identify new bioactive lipids which are deregulated in the colon tissues of obese mice.
To explore further, the researchers conducted another study in both lean and obese mice who had experimentally-induced colon inflammation. They used molecular analyses to follow a pathway called Wnt because about 90 percent of sporadic colorectal cancers have activating mutations within the Wnt pathway, the professor notes. They found that obesity increases activation of Wnt signaling in the colon, but it too can be eliminated by the two different inhibitors and the knockout.