Ordinarily, microRNAs are evaluated in terms of their expression levels. Relatively little notice is taken of the molecules’ methylation status. Yet methylation status may matter. That is, it may affect the biological activity of microRNAs, including activity related to cancer. When this possibility was investigated by scientists based at Osaka University, microRNA methylation—an epitranscriptomic modification—was found to have value as a cancer biomarker.
To evaluate the cancer biomarker potential of microRNA methylation, scientists led by Hideshi Ishii, MD, PhD, professor in the department of cancer profiling discovery, measured levels of methylated microRNAs and assessed whether abnormal levels correlated with cancer. The scientists were careful to remain open to any sort of microRNA methylation. Instead of using conventional detection methods, which are sensitive only to preestablished RNA modifications, the scientists used matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF), a nontargeted detection technique. Doing so allowed the scientists to identify novel methylated cytosines and adenines in several mature microRNAs in cancer cell lines, human tissues, and serum.
“While we found methylated microRNA in the samples from pancreatic cancer patients, it was either present in very low levels or absent in the control group,” said Ishii. “Further, methylation levels in serum samples were able to distinguish early pancreatic cancer patients from healthy controls.”
Additional findings appeared August 29 in the journal Nature Communications, in an article titled, “Distinct methylation levels of mature microRNAs in gastrointestinal cancers.” Besides suggesting a basis for diagnostic strategies for early-stage cancer, the article speculates that methylation assessments could add a dimension to our understanding of microRNA biology. By uncovering mechanisms that could explain how microRNA methylation contributes to cancer, scientists could find ways to develop targeted therapies.
“Here we show that a fraction of mature miRNAs including miR-17-5p, -21-5p, and -200c-3p and let-7a-5p harbor methyl marks that potentially alter their stability and target recognition,” the article’s authors wrote. “Importantly, methylation of these miRNAs was significantly increased in cancer tissues as compared to paired normal tissues. Furthermore, miR-17-5p methylation level in serum samples distinguished early pancreatic cancer patients from healthy controls with extremely high sensitivity and specificity.”
“Our data indicate that levels of methylated microRNA may be more useful than those of microRNA as a biomarker for gastrointestinal cancer,” added Jun Koseki, PhD, assistant professor in the department of cancer profiling discovery and co-lead author of the paper. “Clarifying the mechanisms by which methylation regulates microRNA function throughout the different stages of cancer may facilitate the development of targeted therapies, leading to improved patient outcomes.”
As early detection and treatment of cancer can have a substantial effect on patient outcome, new ways to screen for cancer could be vitally important. Given the advantages with respect to existing biomarkers for cancer, it is possible that RNA methylation will be an important component of future systems for early cancer detection.