Polysome Screen Identifies Cancer Related MicroRNAs

An international research team has developed a polysome-based method for detecting microRNAs (miRNAs) that act to promote or sustain growth of malignant mesothelioma and other types of cancer.

MicroRNAs are short RNA molecules about 22 nucleotides in length. Essentially, miRNAs specifically target certain messenger RNAs (mRNAs) to prevent them from coding for a specific protein. The expression of miRNAs in cancer has been widely studied and has allowed this activity to be classified as oncomir (also oncomiR) or oncosuppressor.

The dysregulation of oncomirs has been associated with specific cancer forming events such as malignant transformation and metastasis. Some oncomir genes are oncogenes, in that overexpression of the gene leads to cancerous growth. Other oncomir genes are tumor suppressors in a normal cell, so that under expression of the gene leads to cancerous growth.

In order to identify biologically active oncomirs, investigators at the National Institute of Molecular Genetics (Milan, Italy) and their collaborators in Italy and the United States developed a screen for miRNAs acting on the polysomes of malignant mesothelioma (MPM) cells. A polysome (or polyribosome) is a complex comprising an mRNA molecule and two or more ribosomes that act to translate mRNA instructions into polypeptides.

They investigators reported in the August 2, 2018, online edition of the journal Cancer Research that only a small percentage of expressed miRNAs physically associated with polysomes. On polysomes, they identified miRNAs already characterized in MPM, as well as novel ones like miR-24-3p, which acted as a pro-migratory miRNA in all cancer cells tested. They found that miR-24-3p positively regulated the activity of the enzyme Rho-GTP, a kinase involved in regulating the shape and movement of cells by acting on the cytoskeleton. In contrast, inhibition of miR-24-3p reduced growth in MPM cells.

Among the specific targets of miR-24-3p was cingulin, a tight junction protein that inhibited Rho-GTP activity. Overexpression of miR-24-3p was found to only partially inhibit cingulin mRNA but to completely eliminate cingulin protein, confirming its action via translational repression. This finding confirmed that miR-24-3p was an oncomir, and suggested that identification of polysome-associated miRNAs efficiently sorted out biologically active miRNAs from inactive ones.

“We have identified a novel approach for identifying relevant miRNA in cancer biology,” said senior author Dr. Stefano Biffo, professor of cell biology at the University of Milan (Italy) and group leader at the National Institute of Molecular Genetics. “By examining the polyribosomes where translation occurs, this "focused" search has allowed us to identify that miR-24-3p (a particular miRna) expression is relevant to cancer progression and metastasis.”

Related Links:
National Institute of Molecular Genetics
University of Milan