Scientists found that the molecule microRNA 135b is a vital ‘worker’ employed by several important cancer genes to drive the growth of colorectal cancers (CRCs). Drugs targeted at the microRNA could knock out the effects of multiple cancer-causing mutations at once, while tests for microRNA could identify patients with the most aggressive disease, the researchers believe.
MicroRNAs are small strands of genetic material that regulate gene activity and are involved many cellular processes. The study showed that a number of known cancer gene mutations, including APC, PI3KCA, SRC, and p53, exercise their effects through microRNA 135b.
The research was carried out by an international team of scientists based at The Institute of Cancer Research in London and the University of Glasgow in Scotland, both in the United Kingdom, and at The Ohio State University in Columbus, Ohio. The work was published in the journal Cancer Cell (2014; 25(4):469-483).
Scientists tested for microRNA 135b in 485 patients with CRC and found that the levels were at least four times higher in tumors compared with healthy tissue, and that patients with the highest levels did not survive as long.
They showed that blocking the microRNA stopped tumor growth in CRC mouse models, and in half of them tumors regressed so dramatically they could no longer be seen by imaging. Mice did not show any side effects as a result of treatment.
Although treatments targeting CRC mutations have been developed, patients often develop treatment resistance. Inhibiting microRNA 135b could be an exciting way to attack cancers while avoiding resistance by blocking the effects of multiple cancer-causing mutations simultaneously.
The findings also suggest that testing levels of microRNA 135b could help identify patients likely to develop aggressive CRC, and who might need the most intensive treatment. Overexpression of microRNA 135b was found to be triggered by loss of the APC gene, deregulation of the PTEN/PI3K pathway, and overexpression of the SRC oncogene. When microRNA 135b was overexpressed, cell proliferation was increased and apoptosis—cell death—was reduced.
“We have shown that a specific microRNA can drive the development of bowel cancers and is a key ‘worker’ responsible for putting into action the instructions from many cancer-causing mutations,” said lead author Nicola Valeri, MD, PhD, of The Institute of Cancer Research. “Patients with the highest levels of this molecule have the most difficult-to-treat cancers, and inhibiting the molecule in mice prevents tumors from growing. Although the research is at an early stage, our findings may have an important impact in the way we treat patients with bowel cancer in the future.”