microRNAs play critical role in healing intestinal wounds caused by
chronic bowel diseases
28 May 2014
A microRNA cluster believed to be important for suppressing colon
cancer, plays a critical role in wound healing in the intestine,
according to research at UT Southwestern Medical Center in the US.
The findings, first discovered in mice and later reproduced in
human cells, could provide a fresh avenue for investigating chronic
digestive diseases, such as colitis and Crohn's disease, and for
potentially repairing damage in these and other disease or injury
Ulcerative colitis and Crohn’s disease — the two most common
inflammatory bowel diseases — 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 colon cancer. Understanding the
cellular pathways involved could eventually lead to potential
“We identified a novel role for microRNAs in regulating wound
healing in the intestine. This finding has important implications
for diseases such as ulcerative colitis 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.
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, published 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
The researchers found that the cells that normally increase their
growth to make repairs, called epithelial cells, 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
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
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
“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 wound
healing in the intestine.” Knocking out miR-143 and miR-145
counteracts that effect.