Mystery gene exposed
Mouse intestine: researchers investigate genes found in stem cells within the intestine, linked to cancers of the gastrointestinal tract.
US-based cell biologists have unveiled stunning images of a little-known gene, the G protein-coupled receptor 182, that could be vital in the fight against cancers of the gastrointestinal tract.
“What makes this so exciting is that it’s completely new,” says Professor Kathleen Caron from the Department of Cell Biology and Physiology at the University of North Carolina School of Medicine.
“There was absolutely nothing known about this protein. I think these findings will be picked up on quickly, and I imagine it’s going to fuel a lot of research on this receptor now,” she says.
Green: the g protein-coupled receptor 182 that could be vital in the fight against gastrointestinal cancers.
G-protein coupled receptors in general are a class of cell-membrane proteins suited for drug development; around 40% of approved drugs already target these proteins.
Researchers now hope that discovery of this new gene will lead to a better understanding of gastrointestinal biology and improving treatments of diseases such as colorectal cancer.
To investigate the protein, Caron and colleagues combined a commercially-available mouse model and a reporter molecule to tag expression of Gpr182 in mice of different stages of development.
Analyses revealed the Gpr182 on cell surfaces within several organs including kidneys, lungs and the heart, as well as stem cells within the intestinal crypt; tube-like depressions that line the intestine.
Intestinal crypt of a mouse. Blue: cell nucleus. Green: GPR 182 localised to stem cells. Red: secretory cells.
Caron and colleagues went onto join forces with researchers from the Scott Magness laboratory at UNC, to understand how Gpr182 is expressed in stem cells.
They discovered that when Gpr182 was suppressed, cellular proliferation tended to increase, suggesting the protein acts a 'brake' on cell proliferation.
As the researchers point out, a mutation that suppresses Gpr182 could enhance cell proliferation.
Optical projection tomography. Green: lymphatics within the gut. Red: enterocytes of gut. Middle of tube: indentations going down to crypts.
"We don't necessarily think this gene is a driver of cancer but it's possible that mutations in the gene could play a role in severity of the cancer," says Caron's PhD student, Daniel Kechele.
To complement mice studies, the researchers also probed the links between Gpr182 and cancer in people, discovering that the expression of the gene was lower in the colons of patients with colorectal cancer relative to healthy colon tissue.
This shows MAPK signaling in a mouse prone to adenoma formation. The fiery red is intense overgrowth and proliferation. White indicates the cell nucleus.
Crucially, the latest results indicate that manipulating Gpr182 expression or activation could offer a new route for cancer treatment, especially cancers that affect the gastrointestinal tract.
Research is published in Journal of Clinical Investigation.