Inhibition of a long noncoding RNA called RMEL3 may help treat melanoma patients, including those with a BRAF mutation, according to a recent study developed by researchers at the University of São Paulo in Brazil.
The study, “RMEL3, a novel BRAFV600E-associated long noncoding RNA, is required for MAPK and PI3K signaling in melanoma,” published in Oncotarget, shows that targeting RMEL3 can reduce the viability of cultured melanoma cell lines by up to 95 percent.
Long noncoding RNAs are molecules that do not contain information to generate a protein but participate in the regulation of gene expression, or in specific signaling pathways in the cell. RMEL3, one of the noncoding RNAs found in cells, is thought to participate in signaling pathways related to cell proliferation and survival.
“Our research suggests RMEL3 is expressed in most cases of melanoma. On the other hand, this RNA is rarely found in other kinds of tumor or even in healthy cells, so it’s a highly specific therapeutic and diagnostic target of considerable promise for development,” Enilza Espreafico, professor at the University of São Paulo’s Ribeirão Preto Medical School and principal investigator of the study, said in a press release.
Using databases with tumor sequencing projects, researchers identified 29 RNA sequences that were only expressed in melanoma cells. The team focused on three genes, RMEL1, RMEL2, and RMEL3, which were found to be expressed in tumor samples from patients and melanoma cell lines. RMEL3 was also found in skin lesions considered premalignant.
Using small RNA molecules that bind RMEL1-3 and induce their degradation, called interference RNA, the team found that RMEL3 inhibition induced the most intense reduction in melanoma cells’ viability.
The investigators silenced RMEL3 in five different cell lines — three with a BRAF mutation known to be associated with cancer, one without BRAF mutation, and one ovarian cancer cell line without the BRAF mutation but that functioned as a control because the cells do not express RMEL3.
“BRAF is the main proto-oncogene associated with the development of melanoma. Roughly 60 percent of cases of this type of cancer involve a mutation of BRAF, which codes for a kinase protein that initiates the MAPK signaling pathway, an important trigger of cell proliferation,” Espreafico said.
The researchers found that RMEL3 inhibition has the most dramatic effect in melanoma cell lines carrying the BRAF mutation. It reduces cell viability up to 95 percent. The melanoma cell line that lacked the BRAF mutation only had a 40 percent decrease in viability upon RMEL3 inhibition.
Currently, researchers are examining the role of RMEL3 by inducing its artificial expression in both melanoma and healthy cells. In addition, they also aimed to access how frequently RMEL3 is expressed in melanoma patients by analyzing nearly 500 melanoma samples.
“We observed that RMEL3 was expressed to a greater or lesser extent in over 90 percent of the melanoma samples available. Together with the fact that it isn’t present in healthy tissue in the rest of the organism, this makes it a very interesting therapeutic target,” Espreafico said.