John F. McDonald, Ph.D., professor, associate dean for biology program development, CSO Ovarian Cancer Institute, and colleagues at the Georgia Institute of Technology separately transfected two miRNAs (miR-7 and miR-128) into the ovarian cancer cell line (HEY) and then monitored global changes in gene expression levels.
While 20% of the changes in expression patterns of hundreds to thousands of genes could be attributed to direct miRNA–mRNA interactions, they reported, the majority of the changes were indirect, involving the downstream consequences of miRNA-mediated changes in regulatory gene expression.
The pathways most significantly affected by miR-7 transfection, the investigators said, are involved with cell adhesion and other developmental networks previously associated with epithelial-mesenchymal transitions and other processes linked with metastasis. In contrast, the pathways most significantly affected by miR-128 transfection are more focused on cell cycle control and other processes commonly linked with cellular replication
Dr. McDonald told GEN that these and other results indicated that changes in patterns of gene expression induced by exogenous miRNA expression are functionally coordinated. “Different families of miRNAs may regulate distinct cellular functions related to cancer. Our findings suggest that miRNAs may be of unique therapeutic value by providing clinicians with a strategy to treat cancer from a systems rather than a single gene perspective.”
According to Dr. McDonald, “Different families of miRNA have evolved over millions of years to coordinate the regulation of hundreds of genes involved in coordinated cellular functions. When cellular functions are disrupted in complex diseases such as cancer, they are optimally treated systemically rather than by a one-gene-at-a–time approach. For this reason, miRNAs may be especially useful as therapeutic agents because they are ‘pre-evolved’ to regulate suites of functionally coordinated genes rather than specific genes that may or may not be critical to function in different cancer patients.”
And, Dr. McDonald, said as with siRNA and other nucleotide drugs, “Another key issue is how we are going to deliver miRNAs therapeutically. Delivery methods have to develop in parallel with the biology. At Georgia Tech we are working with functionalized nanohydrogels as targeted delivery vehicles for siRNAs, and we think they can be designed to effectively deliver miRNAs as well.”
The interest in miRNA research has been good for the research tools market, with, according to Frost & Sullivan, about 20 competitors now offering miRNA microarrays, qRT-PCR, and functional analysis tools. “MicroRNA profiling has already been adopted in cancer research, stem cell research, developmental biology, and neuroscience,” noted Frost & Sullivan research consultant Vinodh Jyotikumar. “This has caused many other fields to develop an interest in auditing their gene-expression analyses or epigenetic research by profiling miRNAs.”
And while clinical applications of miRNAs remain a ways off, basic research continues to reveal a great deal about functional coordination of gene expression.