Transformation of a birthmark
A new molecular mechanism has been discovered that explains why moles become melanomas
Maria Azarova, Naked Science
Melanoma: (a, b) benign melanoma: (c, d) malignant melanoma / © Sebastián Salazar-Colores
Scientists from the University of California, Huntsman Cancer Institute and The University of Utah (USA) has discovered and described a new molecular mechanism that allows us to supplement our data on how moles and melanomas are formed and why the former sometimes become the latter. The study was published in the journal eLife (McNeal et al., BRAFV600E induces reversible mitotic arrest in human melanocytes via microrna-mediated suppression of AURKB).
Moles and melanomas originate from the same pigment cells called melanocytes. The difference is that the so-called nevi are usually harmless: they are formed when melanocytes acquire a specific genetic mutation in the BRAF gene, which encourages cells to divide rapidly. After a while, most moles stop growing and remain harmless. Melanomas are malignant tumors that develop when melanocytes begin uncontrolled growth.
Since most skin melanoma cells still produce melanin, this type of cancer looks like brown or almost black spots on the trunk, head, palms, feet and even under the nails. But some melanomas do not produce melanin, so they may have a pink, brown or even white color. Although such an oncological disease is much less common than others, it is more dangerous because, if not detected at an early stage, it is more likely to spread to other parts of the body.
Changes in the DNA sequence of melanocytes are present in more than 75 percent of moles and 50 percent of melanomas. Scientists believed that when specialized skin cells that produce melanin carry only the BRAFV600E mutation, they stop dividing, leading to the formation of a mole. When they have the BRAFV600E mutation, they divide uncontrollably, eventually becoming melanoma. This was called oncogen-induced cellular aging.
In recent years, researchers have questioned this model, assuming that it does not explain the formation of nevi. "Unlike moles, the mutation that causes melanoma causes melanocytes to divide rapidly to form a tumor that continues to grow indefinitely. It remains unclear why the same mutation in BRAF has such different consequences for moles," the authors of the new work said. And we decided to check out an alternative version.
They analyzed samples of moles and melanomas, compared transcriptomes — the totality of all RNAs that are expressed in the cells of the body — melanocytes of the skin of a healthy person, as well as moles and melanomas formed from them. "We identified a set of microRNAs as highly expressed nevus-enriched transcripts. Two of these microRNAs — MIR211-5p and MIR328-3p — caused mitotic failure, genome duplication and proliferation arrest in human melanocytes through convergent targeting of Aurora kinase B. BRAFV600E causes a similar proliferation arrest in primary human melanocytes. BRAFV600E expression stimulates either arrest or proliferation, depending on the differentiation of melanocytes," the researchers write.
Thus, an increase in MIR211-5p and MIR328-3p levels in skin melanocytes stopped cell division by inhibiting Aurora B kinase: consequently, these microRNAs are responsible for completing the growth of moles. Scientists introduced a mutated form of BRAF into the cells, which acted as a switch — and the nevi also stopped increasing, but a change in the environment surrounding the cells allowed the melanocytes to begin dividing again. External signals from the skin set the direction — to share uncontrollably or to stop this process.
It was possible to suppress the growth of melanoma cells with a mutated form of BRAF using a drug called barasertib, an Aurora B kinase inhibitor. In future studies, scientists plan to find out whether it is possible to stop the development of cancerous tumors and even prevent their formation. "The origin of melanoma, depending on environmental signals, gives a new perspective on prevention and treatment. It also plays a role in the fight against cancer, preventing it and targeting genetic mutations," the authors concluded.
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