Internal Influences on the Risk of Colon Cancer, Colitis

Isoform stabilizing drug may be effective targeting colitis and colon cancer.

The distribution of 2 transcription factors in the colon affects the risk for developing colon cancer and colitis.

It’s well known that the transcription factor hepatocyte nuclear factor 4-alpha (HNF4-alpha) plays a key role in colitis and colon cancer. HNF4-alpha comes in 2 major isoforms, P1-HNF4-alpha (P1) and P2-HNF4-alpha (P2), but how they are distributed in the gut has been unclear.

In a study published in eLife, researchers have been able to determine the distribution of these isoforms in the colon. Researchers reported that maintaining the balance of P1 and P2 is critical for reducing the risk of developing these diseases.

“P1 and P2 have been conserved between mice and humans for 70 million years,” said lead researcher Frances M. Sladek. “Both isoforms are important and we want to keep an appropriate balance between them in our gut by avoiding foods that would disrupt this balance and consuming foods that help preserve it. What these foods are is our next focus in the lab.”

Since P1 and P2 perform non-redundant functions in the intestine, using a drug that targets both may not be as effective.

“Our study also suggests that finding a drug to stabilize 1 isoform should be more effective than targeting both isoforms for treating colitis and colon cancer,” said first study author Karthikeyani Chellappa.

During the study, researchers found that the P1-positive cells resided in the surface lining and the top portion of the crypt, while the P2-positive cells resided mostly in the proliferative compartment in the lower half of the crypt.

Genetically engineered mice were used in the study that had either P1 or P2 solely. The mice were subjected to a carcinogen, and then to an irritant that stressed the colon’s epithelial lining.

The results showed that the P1 mice had fewer tumors than wildtype control mice, while P2 mice had more tumors. When the P1 mice were treated to the irritant alone, they were resistant to colitis, but the P2 mice were found to be much more susceptible.

Next, researchers invoked the barrier function generated by the colon’s epithelial cells that prevent gut bacteria from entering the body. They found that the barrier function was enhanced in P1 mice, while the P2 mice showed a compromised barrier function that researchers presumed allowed bacteria to pass through.

When researchers examined the genes expressed in the P1 and P2 mice, they found that the signaling molecule of the immune system called RELM-beta, which is expressed in the GI tract and in colitis, was expressed more in the P2 mice compared to the P1 mice.

“This makes sense since a reduced barrier function means bacteria can go across the barrier, which activates RELM-beta,” Sladek said. “We also found that the P2 protein transcribes RELM-beta more effectively than the P1 protein.”

Future plans for the researchers will involve a project aimed at understanding how diet effects P1 and P2 gut distribution. They also plan to investigate how obesity and colitis are linked.

“In the case of colitis, could soybean oil be playing a part in allowing bacteria to get across the barrier function?” said second study author Poonamjot Deol. “We do not know. We know its detrimental effect on obesity. But more research needs to be done where colitis is concerned.”