Researchers have identified a key protein that supports the growth of many bowel cancers, paving the way for development of new therapies to combat the deadly disease.
The study, published in the Journal of Cell Biology, revealed that a protein called Importin-11 transports the cancer-causing protein beta-catenin into the nucleus of colon cancer cells, where it can drive cell proliferation.
Inhibiting this transport step could block the growth of most colorectal cancers -- also called bowel cancers -- caused by elevated beta-catenin levels. Around 80 per cent of colorectal cancers are associated with mutations in a gene called APC that result in elevated levels of the beta-catenin protein.
This increase in beta-catenin is followed by the protein's accumulation in the cell nucleus, where it can activate numerous genes that drive cell proliferation and promote the growth and maintenance of colorectal tumours. But how beta-catenin enters the cell nucleus after its levels rise is poorly understood.
"Because the molecular mechanisms underlying beta-catenin nuclear transport remain unclear, we set out to identify genes required for continuous beta-catenin activity in colorectal cancer cells harbouring APC mutations," said Stephane Angers, Professor at the University of Toronto in Canada.
Using CRISPR DNA editing technology, the researchers developed a new technique that allowed them to screen the human genome for genes that support beta-catenin's activity in colorectal cancer cells after its levels have been elevated by mutations in APC.
Angers and colleagues found that Importin-11 binds to beta-catenin and escorts it into the nucleus of colorectal cancer cells with mutations in APC. Removing Importin-11 from these cells prevented beta-catenin from entering the nucleus and activating its target genes.
The researchers discovered that Importin-11 levels are often elevated in human colorectal cancers. Moreover, removing Importin-11 inhibited the growth of tumours formed by APC mutant cancer cells isolated from patients.
"We conclude that Importin-11 is required for the growth of colorectal cancer cells," Angers said. Learning more about how Importin-11 transports beta-catenin into the nucleus may help researchers develop new therapies that block this process and reduce the growth of colorectal cancers caused by mutations in APC.
