Aberrant expression of microRNA (miRNA) in human cancers is a common phenomenon. miRNAs regulate many tumor suppressor genes and oncogenes, therefore acting as oncogenes or tumor suppressor genes themselves to directly regulate cancer cell survival and proliferation.
In tumor cells, inhibiting miRNAs that are overexpressed, and restoring intracellular levels of those that are lost or otherwise underexpressed, are attractive approaches for cancer treatment. Additionally, the role miRNAs play in modulating cancer cell response to chemotherapeutic agents suggests that they may be a target for improving drug response in cancer therapy.
These naturally occurring 19–23 nucleotide long, single-stranded noncoding RNAs, which regulate gene expression largely by decreasing levels of target messenger RNAs, were highlighted at the recent Select Biosciences “Genomics Research” conference.
“As we start to look at the full genomic pattern of a tumor tissue as opposed to a normal tissue we see lots of changes over the course of tumor development. miRNA likely has hundreds of targets in the cell. The goal is to identify specific mutations and pair those with drugs that inhibit or activate pathways,” explained Anthony Saleh, Ph.D., IRTA scientist, National Institute on Deafness and Other Communication Disorders at NIH.
To determine the targets, researchers use genomic, transcriptomic, or proteomic approaches. The difficulty with omics-type experiments is the scope. Myriad miRNAs are overexpressed in cancer, although most are not very highly overexpressed. Targets are painstakingly narrowed down by expression level, consistent expression levels across samples, and biological function.
“We study miRNA expression in head and neck squamous cell carcinoma (HNSCC) lines grown from patients’ tumors and have identified a number of overexpressed miRNAs that are potentially oncogenic, in particular the miR-30 family,” continued Dr. Saleh.
“Other studies showed NF-kappaB was activating expression. NF-kappaB is, in general, an oncogene, promoting tumor formation. We also identified TP53 and Notch1, which are important tumor suppressors for HNSCC, as miR-30 targets. So in HNSCC miR-30 is being stimulated by an oncogene and suppressing two important tumor suppressor pathways.”
TP53, the most common tumor suppressor pathway, primarily functions to direct cell fate decisions. In 90% of HNSCC cases, TP53 is nonfunctional, deleted, or mutated.
Notch1 has different roles in different cancers and highlights the difficulty in studying cancer. In HNSCC it is a tumor cell suppressor. In other cancers it is an oncogene.
“Now we are determining if miR-30 might be a potential target for sensitizing tumors. If we decrease the levels of miR-30 through inhibitors, we may be able to slow down the cancer growth and, perhaps, kill it in combination with other chemotherapeutic drugs or radiation,” concluded Dr. Saleh.