Wound-healing role for microRNAs in colon offer new insight to inflammatory bowel diseases

May 23, 2014

A microRNA cluster believed to be important for suppressing colon cancer has been found to play a critical role in wound healing in the intestine, UT Southwestern cancer researchers have found.

The findings, first discovered in mice and later reproduced in human cells, could provide a fresh avenue for investigating chronic digestive diseases and for potentially repairing damage in these and other disease or injury settings.

"We identified a novel role for microRNAs in regulating wound healing in the intestine. This finding has important implications for diseases such as and Crohn's disease and may be relevant to wound healing mechanisms in other tissues," said Dr. Joshua Mendell, CPRIT Scholar in Cancer Research, Professor of Molecular Biology, and member of the UT Southwestern Harold C. Simmons Cancer Center.

Ulcerative colitis and Crohn's disease—the two most common inflammatory bowel diseases affecting an estimated 1.5 million in the U.S.—stem from an abnormal immune response, which results in the body mistakenly attacking cells in the intestine. The resulting chronic injury to the colon also is considered a risk factor for . Understanding the cellular pathways involved could eventually lead to potential therapeutic treatments.

MicroRNAs serve as brakes that help regulate how much of a protein is made, which, in turn, determines how cells respond to various stimuli. Approximately 500 to 1000 microRNAs are encoded in the genomes of mammals. Dr. Mendell's laboratory studies how these tiny regulators work normally and how diseases such as cancer arise when they function in an abnormal manner.

These latest findings, which appear in the journal Cell, focus on two microRNAs: miR-143 and miR-145. While there is extensive literature implicating these microRNAs in colon cancer, little is known about their natural function in the colon. So Dr. Guanglu Shi, postdoctoral researcher in Molecular Biology, and other researchers began their five-year investigation by removing or "knocking out" the gene that produces these two microRNAs in mouse models.

The researchers found that the cells that normally increase their growth to make repairs, called , fail under stress in the knockout animals. Epithelial cells line the intestines where food is digested, separating the contents from the rest of the body and absorbing needed nutrients.

"The epithelial cells of the colon normally proliferate quickly to fill in the wounds from an injury. Without these microRNAs, the epithelial cells are unable to switch into this repair mode, so they never heal the wounds and the mice are not able to survive," Dr. Shi said.

In addition, the research upended traditional thinking about where the tiny microRNAs reside, discovering to everyone's surprise that they reside in supporting cells, called mesenchymal cells, instead of the epithelial cells themselves as previously thought.

"This was surprising because colon cancers derive from the epithelial cells, so it was assumed that the microRNAs must function within them," Dr. Mendell said. "If these microRNAs do participate in colon cancer, they must do so by acting from outside the epithelium."

Identifying the accurate location of the microRNAs is essential to locating the pathways they regulate and eventually, to determining whether they can be manipulated for therapeutic purposes.

Dr. Mendell's team collaborated with a group of surgeons at UT Southwestern including Dr. Joselin Anandam, Assistant Professor of Surgery, Dr. Abier Abdelnaby, Assistant Professor of Surgery, Dr. Glen Balch, Assistant Professor of Surgery, and Dr. John Mansour, Assistant Professor of Surgery, and Dr. Adam Yopp, Assistant Professor of Surgery, who provided human tissue specimens. "The ability to work closely with an outstanding clinical team enabled us to confirm that our findings in mice extend to humans," Dr. Mendell said.

In addition, the researchers say they have worked out one of the many pathways regulated by these microRNAs, called the insulin-like growth factor signaling pathway.

"This pathway is involved in many different processes in the body, but one function is to stimulate wound healing responses," Dr. Mendell explained. "Increasing the amount of insulin-like growth factor signaling improves in the intestine."

Knocking out miR-143 and miR-145 counteracts that effect.

Explore further: Worldwide gene mapping boosts leukaemia research

Related Stories

Worldwide gene mapping boosts leukaemia research

May 20, 2014
An international project has mapped for the first time the sets of genes used in virtually every cell in the human body, boosting the resources of WA leukaemia researchers.

Team discovers new mechanism allowing tumor cells to escape immune surve

March 18, 2014
The immune system plays a pivotal role in targeting cancer cells for destruction. However, tumor cells are smart and have developed ways to avoid immune detection. A collaborative team of researchers at Moffitt Cancer Center ...

Understanding aspirin's effect on wound healing offers hope for treating chronic wounds

May 12, 2014
In addition to its known capacity to promote bleeding events, aspirin also inhibits wound healing. New research published in The Journal of Experimental Medicine now describes how aspirin acts on key skin cells called keratinocytes, ...

Potential therapeutic target for wound-healing and cancer identified

May 12, 2014
A Jackson Laboratory research team led by Professor Lenny Shultz, Ph.D., reports that a protein involved in wound healing and tumor growth could be a potential therapeutic target.

Recommended for you

Alternative splicing, an important mechanism for cancer

September 22, 2017
Cancer, which is one of the leading causes of death worldwide, arises from the disruption of essential mechanisms of the normal cell life cycle, such as replication control, DNA repair and cell death. Thanks to the advances ...

'Labyrinth' chip could help monitor aggressive cancer stem cells

September 21, 2017
Inspired by the Labyrinth of Greek mythology, a new chip etched with fluid channels sends blood samples through a hydrodynamic maze to separate out rare circulating cancer cells into a relatively clean stream for analysis. ...

Whole food diet may help prevent colon cancer, other chronic conditions

September 21, 2017
A diet that includes plenty of colorful vegetables and fruits may contain compounds that can stop colon cancer and inflammatory bowel diseases in pigs, according to an international team of researchers. Understanding how ...

Drug combination may improve impact of immunotherapy in head and neck cancer

September 21, 2017
Checkpoint inhibitor-based immunotherapy has been shown to be very effective in recurrent and metastatic head and neck cancer but only in a minority of patients. University of California San Diego School of Medicine researchers ...

New kinase detection method helps identify targets for developing cancer drugs

September 21, 2017
Purdue University researchers have developed a high-throughput method for matching kinases to the proteins they phosphorylate, speeding the ability to identify multiple potential cancer drug targets.

Brain cancer growth halted by absence of protein, study finds

September 20, 2017
The growth of certain aggressive brain tumors can be halted by cutting off their access to a signaling molecule produced by the brain's nerve cells, according to a new study by researchers at the Stanford University School ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.