Advances in miRNA
Melanoma is associated with abnormal patterns of microRNA (miRNA) and large noncoding RNA (lncRNA) gene expression. Ranjan Perera, Ph.D., associate professor at Sanford-Burnham Medical Research Institute, is deciphering how miRNAs and lncRNAs impact development of this disease.
“As master regulators of hundreds of RNAs, miRNAs have been implicated in a number of malignancies. Because they may be either upregulated or downregulated, we are examining the possibility of using miRNA and lncRNAs as biomarker and discovery tools. As biomarkers, they may be useful for early prognostics or diagnostics. As discovery tools, they could be employed as therapeutics targeting certain genes or even to assist with gene-function discovery.”
Dr. Perera first looked at the miRNA signatures between normal and malignant melanocytes and melanoma cell lines. “Our gene-expression studies identified a handful of miRNAs that were downregulated. One of these is miR-211. While normal cells expressed miRNA-211, malignant cells did not. Thus, our basic hypothesis is that miRNA-211 downregulation in melanocytes induces human melanoma.”
By putting miR-211 back into melanoma cells, Dr. Perera and his team found that it blocked tumor growth and invasion. To begin to dissect the mechanism, he performed functional studies. “We found that miR-211 targets the KCNMA1 gene that codes for the so-called potassium large conductance calcium-activated channel, subfamily M, alpha member 1,” he said.
“Next, we found that miR-211 resides in the intron of TRPM1, which encodes a calcium-channel protein called the transient receptor potential cation channel subfamily M member 1 protein. The expression of TRPM1 is inversely correlated with melanoma aggressiveness, suggesting that it suppresses the metastasis of melanoma cells.”
Finally, Dr. Perera’s team found that the expression of miR-211 is regulated via TRPM1 gene that is regulated by MITF, which encodes the microphthalmia-associated transcription factor. He summarized his findings: “When we utilized siRNAs to knockdown the expression of MITF, we found that both TRPM1 and miR-211 were also knocked down.”
“We are now able to build a new signal-transduction pathway that may ultimately provide information for early melanoma prognostics,” Dr. Perera explained. “My team and others are evaluating patient samples and have already demonstrated that indeed miR-211 is associated with human melanomas.”