A group of researchers at the Ohio State University Comprehensive Cancer Center (OSUCCC) has discovered that a certain type of RNA, microRNA-155, may provide the link between inflammation and cancer. The article describing the study was published online ahead of print in the Proceedings of the National Academy of Science in March (doi: 10.1073/pnas.1101795108).
Many studies have linked chronic inflammation with cancer (ie, inflammatory bowel disease and colorectal cancer), and some estimate that as many as 25% of cancer cases are caused by chronic infection. This study, led by Carlo Croce, showed that inflammation stimulates a rise in levels of micro-RNA-155 (miR-155), and that this, in turn, causes a drop in levels of the proteins involved in DNA repair and results in a higher rate of the spontaneous gene mutations that can lead to cancer.
First author and post-doctoral researcher Esmerina Tili said, “Our study shows that miR-155 is upregulated by inflammatory stimuli and that overexpression of miR-155 increases the spontaneous mutation rate, which can contribute to tumorigenesis. People have suspected for some time that inflammation plays an important role in cancer, and our study presents a molecular mechanism that explains how it happens.”
MicroRNAs are involved in many important cell processes and act by suppressing the amounts of certain proteins; each type of microRNA can affect many different proteins. MiR-155 is known to influence blood-cell maturation, immune responses, and autoimmune disorders, and high levels of the molecule have been directly linked to the development of leukemias as well as breast, lung, and gastric cancers.
In the study, Tili and her colleagues examined the effects of inflammation-promoting substances such as tumor necrosis factor or lipopolysaccharide on miR-155 expression and on the frequency of spontaneous mutations in several breast-cancer cell lines. When the researchers exposed breast-cancer cells to the two inflammatory factors, the levels of miR-155 rose to abnormally high levels, and the mutation rate increased two- to three-fold. To understand why, the investigators focused on WEE1, a kinase that stops the process of cell division to allow damaged DNA to be repaired.
The investigators learned that miR-155 also targets WEE1 and showed that high levels of miR-155 lead to low levels of WEE1. They reasoned that low levels of WEE1 allowed cell division to continue even when DNA damage is present, and that this leads to an increased number of mutations.
“Our study suggests that miR-155, which is associated with inflammation, increases the mutation rate and might be a key player in inflammation-induced cancers generally,” said principal investigator Dr. Carlo M. Croce, professor and chair of molecular virology, immunology and medical genetics, and director of the Human Cancer Genetics program at the OSUCCC – James Cancer Hospital. “This could make miR-155 an important therapeutic target.”