About 90% of cancer-related deaths are attributed to metastasis, events where cancer migrates from its original source other sites in the body. Why some cancers have a higher propensity to spread and how they do so is a hot topic of cancer biology.
A recent report helped to shed some light on this matter. Researchers identified a key protein, MARK4, which enables cancer cells to break off and colonize at distant sites. More importantly, these researchers identified the corresponding micro-RNA – a silencer molecule – that acts to repress MARK4 and thus reduces metastasis. The results offer a new target for anticancer therapy, as well as a potential biomarker for predicting the likelihood of metastasis for any given patient.
In studying breast and lung cancer tissues, researchers honed in on a protein that seemed to aid cancer metastasis. The protein is a kinase made from the gene known as MAP/microtubule affinity regulating kinase 4, or MARK4, and is involved in cell cycle control. The exact mechanism of how MARK4 enables cancer cells to break off and travel to distant sites in the body is still being investigated.
But researchers did find that MARK4 expression is silenced by a micro-RNA known as miR-515-5p. Micro-RNAs (miRNAs) are short, non-coding RNA sequences that regulate gene expression by binding at the 3’-untranslated region of a target. In this case, miR-515-5p binds to the end of the MARK4 transcript and prevents its expression.
The researchers confirmed this in a cell culture model of breast and lung cancer. They observed the same results in a metastatic cancer mouse model, where increasing the amount of miR-515-5p reduced tumor spread. Consistent with their expectations, the researchers found lower amounts of this micro-RNA in tumors that had already spread throughout the body.
For cancer, survival rate is inversely correlated with metastasis. Thus, lower amounts of the silencer miRNA are likely correlated lower survival, as metastasis risks are higher. Indeed, researchers found lower survival rates when they examined breast and lung cancer patients who expressed low levels of miR-515-5p.
“In our work we have shown that this silencer molecule is important in the spread of cancer. This is very early stage research, so we now need more studies to find out more about this molecule, and if it is present in other types of cancer," said Justin Stebbing, professor at the Imperial College London and senior study author.
The results provide two avenues of molecular targets for cancer therapy. Researchers could target MARK4 to block its expression or otherwise stop it from promoting cancer cell proliferation. In the same vein, researchers could target miR-515-5p, either by increasing its expression or affinity to the MARK4 transcript. In these scenarios, the goal is to dampen MARK4 expression so as to prevent cancer cell migration outside of its primary site.
Another implication from these results will be a potentially new diagnostic tool for the prediction of cancer metastasis. Since metastasis is correlated to the levels of MARK4 and miR-515-5p, a test that accurately measures these biomarkers could reveal to doctors the likelihood of the cancer spreading. This will guide future treatments for the patients, and hopefully increase survival outcomes.
Additional source: EurekAlert!