RNA against metastases

Microregulatory RNAs inhibit breast cancer metastases

Kirill Stasevich, "Science and Life", based on MIT materials: Gene therapy technique may help prevent cancer metastasis

The cell controls the activity of its own genes with the help of various tools, and one of them is the so–called microregulatory RNAs. More often we hear about matrix, or informational, RNAs, which are copies of genes recorded in DNA.

The matrix RNA synthesized in the cell nucleus, after additional molecular procedures, is sent to the cytoplasm, where protein-synthesizing machines – ribosomes – sit on it and begin to assemble the polypeptide chain in accordance with the sequence of genetic "letters" and "words". In other words, matrix RNAs encode proteins.

But besides them, there are many more varieties of RNA that do not encode anything. Some of these non–coding RNAs have been known for a very long time - for example, ribosomes are a complex complex of ribosomal RNAs on which ribosomal proteins sit. Some of the non-coding RNAs were discovered relatively recently, and subsequently it turned out that they affect the activity of matrix RNAs. What does "affect activity" mean?

We have just said that RNA matrices serve as instructions for protein synthesizing machines; and if we see that many protein molecules are synthesized on RNA copied from one gene, and few protein molecules are synthesized on RNA copied from another gene, then we say that the first RNA is more active than the second. And regulatory RNAs (they are usually called microregulatory RNAs or microRNAs – because of their small size) are able to reduce the activity of matrices, turn off protein synthesis on them. It is known that they bind to matrix RNAs in certain areas that are important for the interaction of the matrix with the protein-synthesizing apparatus, and thereby prevent this apparatus from working.

There were more and more examples of how microRNAs control the activity of genes (controlling the activity of matrix copies ultimately affects the activity of the gene itself stored in DNA), and eventually among them were found those that are related to oncological diseases.

Indeed, it is easy to imagine how regulatory RNAs can provoke or, conversely, protect us from cancer: if there are a lot of microRNAs in the cell that suppress the synthesis of oncogenic protein, then malignant degeneration of such a cell is not threatened; if microRNAs turn off protein synthesis, which itself ensures that the cell does not become cancerous, then Obviously, such regulatory RNA will increase the likelihood of tumor development. (We once wrote that cancer cells with the help of their microRNAs can even make other, quite healthy cells malignant.) Over time, works began to appear in which both methods of oncodiagnostics by microRNA and methods of treatment were proposed.

The authors of a recent article in Nature Communications (Gilam et al., Local microRNA delivery targets Palladin and prevents metastatic breast cancer) suggest using microRNAs to suppress metastasis of breast cancer, which is notorious for its tendency to spread to other tissues. Earlier, Noam Shomron from Tel Aviv University and his colleagues managed to show that certain changes in the DNA of cancer cells increase the aggressiveness of the tumor, and since these genetic changes were manifested in an increase in the level of some intracellular proteins, the idea arose that mutations prevent microRNAs from suppressing the synthesis of protein molecules that stimulate the disease.

Regulatory RNAs, as we have said, interact with certain regions of matrix RNAs. The researchers analyzed the regions of the genome corresponding to those zones in the matrix RNAs with which microRNAs bind, while paying special attention to the genes responsible for cellular mobility – because metastatic cells move very well; in addition, they took into account information on characteristic metastatic mutations.

It turned out that among the many such mutations there is one that has a particularly strong effect on the aggressiveness of the tumor, and it is found in cancer cells in the Palladin gene, which has long been known for the fact that its activity stimulates the migration of malignant cells. As for the mutation, it does not allow two microregulatory RNAs, miR–96 and miR-182, to bind to the matrix RNA of the Palladin gene. That is, normally miR-96 and miR-182 sit on the RNA from the "migration gene" and thereby turn off protein synthesis on it, and the cell remains in place. But because of the mutation, the RNA copy of the "migration gene" remains active, and the malignant cell goes on its way.

All this was confirmed experimentally: when the aforementioned microRNAs were injected into breast cancer cells with unmutated Palladin, the cells did not show any metastatic impulses. However, the authors of the work did not stop there: Shomron, together with the staff of the Massachusetts Institute of Technology, managed to show that miR-96 and miR-182 microRNAs can be used for anti-cancer therapy.

If the "migration gene" and, accordingly, the matrix RNA that is read from it carry a mutation, then it is necessary to edit the microregulatory RNAs accordingly and introduce them into the tumor. Judging by the results of experiments on mice, modified microRNAs are really able to stop metastasis: therapeutic synthetic microRNA molecules were enclosed in nanoparticles that delivered microRNAs directly to the address inside the sick animal, that is, to the breast tumor. The same nanoparticles were also loaded with a chemotherapeutic drug, which also reached directly to the malignant cells, and as a result, the tumor not only stopped metastasizing, but also slowed down its growth.

Of course, we know that cancer cells demonstrate rare genetic diversity, adapting to new conditions – for example, you can imagine that cells will appear in a tumor that will have mutations in the same Palladin gene that will allow you to ignore medicinal microRNAs. However, genetic analysis is becoming faster and cheaper these days, as well as the synthesis of macromolecules, so in principle, if we have a working therapeutic method with microRNAs in our hands, it can be used against a variety of tumor variants, simply taking those microRNAs that should work in this particular case.

Portal "Eternal youth" http://vechnayamolodost.ru  26.09.2016