Benign melanocytic nevi frequently emerge when an acquired BRAFV600E mutation triggers unchecked proliferation and subsequent arrest in melanocytes. Recent observations have challenged the role of oncogene-induced senescence in melanocytic nevus formation, necessitating investigations into alternative mechanisms for the establishment and maintenance of proliferation arrest in nevi. We compared the transcriptomes of melanocytes from healthy human skin, nevi, and melanomas arising from nevi and identified a set of microRNAs as highly expressed nevus-enriched transcripts. Two of these microRNAs-MIR211-5p and MIR328-3p-induced mitotic failure, genome duplication, and proliferation arrest in human melanocytes through convergent targeting of AURKB. We demonstrate that BRAFV600E induces a similar proliferation arrest in primary human melanocytes that is both reversible and conditional. Specifically, BRAFV600E expression stimulates either arrest or proliferation depending on the differentiation state of the melanocyte. We report genome duplication in human melanocytic nevi, reciprocal expression of AURKB and microRNAs in nevi and melanomas, and rescue of arrested human nevus cells with AURKB expression. Taken together, our data describe an alternative molecular mechanism for melanocytic nevus formation that is congruent with both experimental and clinical observations.
Keywords: cancer biology; genetics; genomics; human; melanocytes; melanoma; microRNA; nevi.
Lots of people have small dark patches on their skin known as moles. Most moles form when individual cells known as melanocytes in the skin acquire a specific genetic mutation in a gene called BRAF. This mutation causes the cells to divide rapidly to form the mole. After a while, most moles stop growing and remain harmless for the rest of a person’s life. Melanoma is a type of skin cancer that develops from damaged melanocytes. The same mutation in BRAF that is found in moles is also present in half of all cases of melanoma. Unlike in moles, the melanoma-causing mutation makes the melanocytes divide rapidly to form a tumor that keeps on growing indefinitely. It remains unclear why the same genetic mutation in the BRAF gene has such different consequences in moles and melanomas. To address this question, McNeal et al. used genetic approaches to study melanocytes from moles and melanomas. The experiments identified some molecules known as microRNAs that are present at higher levels in moles than in melanomas. Increasing the levels of two of these microRNAs in melanocytes from human skin stopped the cells from growing and dividing by inhibiting a gene called AURKB. This suggested that these microRNAs are responsible for halting the growth of moles. Introducing the mutated form of BRAF into melanocytes also stopped cells from growing and dividing by inhibiting AURKB. However, changing the environment surrounding the cells reversed this effect and allowed the melanocytes to resume dividing. In this way the mutated form of BRAF acts like a switch that allows melanocytes in skin cancers to start growing again under certain conditions. Further experiments found that a drug called barasertib is able to inhibit the growth of melanoma cells with the mutant form of BRAF. Future work will investigate whether it is possible to use this drug and other tools to stop skin cancer tumors from growing, and possibly even prevent skin tumors from forming in the first place.
© 2021, McNeal et al.