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At AACR, Researchers Highlight Multiple Roles of microRNAs in Cancer

SAN DIEGO (GenomeWeb News) — MicroRNAs are cropping up in different aspects of cancer research, according to a session at the American Association for Cancer Research annual meeting held here this week.

MicroRNAs can act as oncogenes and as tumor suppressors, and they are increasingly of interest to researchers wanting to inhibit cancer development, develop biomarkers for disease progression, and for potential use as therapeutics, among other endeavors.

"The involvement of microRNAs in cancer is huge," said Muller Fabbri, an assistant professor at the University of Southern California, who co-chaired a session on noncoding RNAs in cancer.

Researchers believe that some miRNAs may inhibit cancer development. For example, Yee Sun Tan, a graduate student at the University of Maryland, presented work showing that miR-509 could inhibit the development of leukemia.

Through a functional screen of a B-cell acute lymphoblastic leukemia cell line, Tan and her colleagues homed in on miR-509 as a candidate inhibitor of leukemia, an effect they confirmed in two other B-ALL cell lines. They then traced the effect of miR-509 to a combination of increased apoptosis and decreased cell cycling.

In addition, Tan described how she and her colleagues searched for miR-509 targets, finding that it interacts with nearly 950 targets, but after filtering for targets expressed in the cell line, genes known to be involved in cell proliferation, and more, they focused on RAB5C, the expression of which was reduced in cells expressing miR-509. Knocking down RAB5C phenocopied the inhibitory effect of overexpressed miR-509 and that, coupled with other lines of evidence, indicated that RAB5C mediates the effect of the miRNA.

Both miR-509 and RAB5C, she said, could be new B-ALL therapeutic targets.

MiRNAs also can break out of tumors and circulate in the bloodstream, much like circulating tumor cells and circulating DNA, noted Evi Liamidou from the University of Athens in Greece. She and her team are evaluating a three-miRNA signature for breast cancer outcomes.

Using a training set of 80 breast cancer patients and 20 healthy controls, she and her colleagues examined the concentrations of miR-21, miR-146a, and mir-210 levels in plasma. Levels of the microRNAs, she said, clearly differed between the patients and controls. They further validated these findings in 54 additional breast cancer patients.

Then by comparing these levels to outcomes using Kaplan-Meier curves, they found that high levels of circulating miR-21 in the plasma was associated with both worse progression-free survival and overall survival; high levels of miR-146a wasn't linked to progression-free survival, though it was with shorter overall survival; and miR-210 was not associated with either.

Circulating miR-21 and miR-146a are promising biomarkers for breast cancer prognosis, Liamidou said, noting that her team will next examine a larger cohort of patients as well as a larger panel of circulating miRNAs.

And miRNAs themselves could be targets of drugs. MiR-21 is a master regulator of pro-oncogenic networks and is upregulated in hepatocellular carcinoma, noted Dmitri Wiederschain from Sanofi Oncology.

He and his colleagues at Sanofi and Regulus have developed single-stranded oligonucleotide inhibitors of miR-21, dubbed anti-miR-21s, that they've tested in a panel of HCC cell lines. These anti-miR21s led to the de-repression of known miR-21 targets ANKRD46, DDAH1, and RECK1, and affected survival in a number of HCC cell lines.

Additionally, in those susceptible cell lines, Wiederschain noted that caspase 3 and caspase 7 were induced, as was apoptosis. Anti-miR-21 also suppressed HCC cell migration in response to hepatocyte growth factor and halted clonogenic expansion of HCC cells.

Through global gene expression profiling of HCC cells treated with anti-miR-21, Wiederschain and his colleagues found that multiple cellular processes were affected by miR-21 inhibition, including metabolic pathways. He also noted that cyclin H is significantly reduced, which he suggested could contribute to the efficacy of anti-miR-21 compounds.