Protein that detects light may play a role in the origin and progression of melanoma, study suggests

Found in skin and retinal cells, melanopsin (OPN4) is a protein that acts as a light sensor. A new study conducted at USP (University of São Paulo) suggests that the molecule may also play a role in the development and progression of melanoma, the most aggressive type of skin cancer.

Through experiments with animals and genetically modified cells, researchers from the Laboratory of Comparative Physiology of Pigmentation of the Department of Physiology of the Institute of Biosciences (IB-USP) showed that the disease progresses more slowly when this protein is not functional. The results were published in the scientific journal Communications Biology, linked to Nature.

Although other groups have already shown that opsins can act on cancers, this is the first finding of its kind for melanoma, which accounts for 5% of malignant skin tumors and 80% of cancer deaths in general.

The study, which was supported by Fapesp (projects 17/24615-5, 17/26651-9, 18/14728-0 and 19/19005-9), originated from a study carried out by the same group with models of melanocytes (skin cells that produce melanin). At the time, researchers showed that melanopsin was not only expressed in these cells but also participated in processes such as pigmentation, adjustment of the biological clock and even cell death caused by ultraviolet A radiation (read more at: agencia.fapesp.br/24130/ ).

In the most recent work, the DNA editing technique known as CRISPR was used to alter the Opn4 gene sequence and create a stable model of melanoma cell with a non-functional version of the protein.

“When we created the knockout cells [sem OPN4 funcional]we noticed that they had a very different phenotype: they grew less and had a reduced proliferative capacity”, says Leonardo Vinícius Monteiro de Assis, author of the study in partnership with José Thalles Lacerda and currently a researcher at the University of Lübeck, Germany. , to ask ourselves and investigate whether melanopsin played a role in melanoma progression or carcinogenesis.”

The theory was confirmed first in in vitro and later in animal studies. Tumor cells that contained the non-functional version of OPN4 grew less and more slowly than wild-type cells (without the modification in OPN4). The finding was later confirmed by a protein analysis technique called proteomics and through analysis of public databases.

“In summary, we demonstrated that in melanoma cancer, when you remove OPN4, there is a reduction in cell growth,” says Assis. “This is basically caused by two pathways that are not necessarily correlated, but could be: an increase in the activation of the immune system for a reason not yet characterized and a very significant reduction in the signaling of proteins called GTPases, which are like small engines that act in cell cycle progression and are greatly reduced in these tumors.”

The study also revealed that a very important transcription factor in melanoma, MITF (microphthalmia-associated transcription factor), is also much less expressed in cells with the non-functional version of melanopsin.

According to Assis, the sum of all the information suggests, for the first time, that melanopsin acts as an oncogene in melanoma, that is, it is associated with the appearance and growth of this type of cancer. Until then, the molecule had never been associated with the development of tumors. However, more experiments with melanoma cell lines and other approaches are still needed to definitively confirm this role.

Perspectives for the future

The Laboratory of Comparative Physiology of Pigmentation, led by scientist Ana Maria de Lauro Castrucci, was one of the few in the world to demonstrate that melanopsin also detects temperature, acting as a thermosensor and photosensor independently, in 2018. Now, with the new information , adds one more important aspect to the topic, showing that these molecules can become promising therapeutic tools in the future.

“Possibly, melanopsin can be explored in the treatment of melanoma and this opens a new branch to investigate its role in other diseases, such as, for example, those of the liver, where opsins are also present”, says Assis.

The current focus of the Laboratory of Comparative Physiology of Pigmentation is precisely to investigate the function of melanopsin in a systemic way, in other organs that are not classically known, such as adipose tissue, liver and heart, among others.