A Brazilian study published in Journal of Pineal Research describes a set of genes potentially regulated by the hormone melatonin in some types of tumors – particularly in the breast. According to the authors, the results may guide future personalized therapies for the disease.
“Some specific types of tumors seem to have a direct relationship with the amount of melatonin produced by cells. Identifying how this hormone intervenes in molecular signaling at the genetic level is essential to guide personalized therapies based on melatonin”, says Luiz Gustavo Chuffa, professor at IBB-Unesp (Botucatu Biosciences Institute, Universidade Estadual Paulista).
The study was supported by FAPESP and included the participation of researchers from Unesp, Uenp (State University of Northern Paraná), from Famerp (Faculty of Medicine of São José do Rio Preto) and the University of Texas Health Science Center, in San Antonio, in the United States.
Known as the sleep hormone, since its functions include the calibration of the biological clock, melatonin has demonstrated anti-tumor properties in laboratory tests. Evidence from the scientific literature indicates that low levels of the hormone are associated with increased risk of cancer. A possible explanation for this phenomenon would be the effect of melatonin on the modulation of gene expression – it could, for example, increase the activity of tumor suppressor genes.
“Most tumor cells have low levels of melatonin. However, when they are treated with this hormone in tests in vitro, there is an increase in the rate of cell death and, on the other hand, a decrease in the rate of proliferation – important mechanisms to prevent tumor progression and metastasis. There are already ongoing clinical trials evaluating melatonin therapy. As there are specific treatments for the different subtypes of breast cancer, it is likely that some patients may respond well to alternative treatments based on melatonin and others cannot “, says the researcher to Agência FAPESP.
In search of target genes
To identify molecular markers capable of guiding cancer therapy, the researchers conducted a first study based on meta-analysis (statistical technique that allows integrating the results of several published studies) to investigate how melatonin regulates the expression of microRNAs in seven tumor types – breast, head and neck, liver, stomach, prostate, central nervous system, colon and rectum.
MicroRNAs are small RNA molecules that do not encode protein, but play a regulatory role in the genome by controlling the expression of genes and, consequently, several cellular processes.
“In this first stage, we found 14 very recent studies that associated melatonin with the alteration in the expression of microRNAs. For the seven types of tumors that we were analyzing, we found 46 microRNAs with altered expression”, he says.
Based on the relationship between microRNAs and their regulatory targets, the researchers performed bioinformatics analyzes to identify pathways associated with hormonal action in tumor cells. Regulatory networks and molecular interactions were generated and analyzed in collaboration with researchers Robson Francisco Carvalho, Luis Antonio Justulin and Sarah Santiloni.
“By crossing the information with the public database TCGA (The Cancer Genome Atlas), we identified the target genes of these 46 microRNAs with altered expression,” says Chuffa.
With these data, it was possible to identify the action of melatonin in several cell signaling pathways. “These melatonin target genes were related to important biological processes in cancer, such as regulation of the cell cycle, cell death and migration and senescence. Melatonin appears to have a greater action on breast, oral and gastric tumors, while prostate tumors , colorectal and glioblastoma showed few changes induced by the described microRNAs “, he explains.
As breast cancer was the tumor type with the most genes and microRNAs involved in this first stage of the study, the researchers compared the target genes of the microRNAs with the data obtained by RNA-seq from breast tumors in mice treated with melatonin.
The RNA-seq technique is part of the set of strategies known as new generation genetic sequencing and its main advantage is the possibility of measuring the expression of several genes at the same time. With this, it is possible to obtain the transcriptome, that is, the complete set of RNA molecules expressed in a tissue.
These analyzes were carried out in partnership with Débora Aparecida Pires de Campos Zuccari and Bruna Victorasso Jardim-Perassi, researchers from Famerp.
“In animals treated with 40 milligrams of melatonin, there was an enrichment of signaling pathways related to the immune system and apoptosis and a decrease in pathways related to aggressiveness and tumor metastasis”, he says.
The group also investigated certain proteins (transcription factors and kinases) active in cellular processes such as transcription and cell cycle. “The objective of this part of the study was to find common targets in cellular processes and in the public database of breast cancer,” he says.
According to Chuffa, the genes regulated by melatonin in breast cancer can be explored as potential targets for the treatment of the disease.
“Given that melatonin is a multitasking molecule, acting on several cellular substrates, we are now deepening this study to understand how this hormone interferes in the expression of microRNAs and, consequently, in the regulation of the identified cellular mechanisms”, he says.