It has recently become clear that abnormal microRNA expression is a very frequent, if not ubiquitous, characteristic of cancer cells. Nevertheless, the mechanisms that govern microRNA expression in normal and pathologic states are poorly understood. Our paper was the first to show that an oncogenic transcription factor directly regulates microRNA expression, providing molecular insight into one mechanism through which microRNAs become dysregulated in cancer.

“...inappropriate activation of a gene that promotes the growth of cells can lead to the development of a tumor.”

Moreover, the specific microRNAs that we studied in this paper have subsequently been shown by multiple laboratories to be frequently overexpressed in cancer cells and to possess oncogenic activity. Thus, our findings have proven to be broadly relevant to our understanding of microRNA regulation and function in disease states.

The discovery that an oncogene regulates microRNA expression provides an entirely new mechanism through which an oncogene can promote tumorigenesis. More generally, c-Myc, the oncogene that we focused on, has been studied for over 20 years, but microRNA regulation represents an entirely new aspect of its function. This emphasizes the potential for many well-studied gene products to have completely unanticipated functions involving microRNAs.

Mechanisms that control when genes are turned on and turned off are critical for maintaining normal cellular behavior. For example, inappropriate activation of a gene that promotes the growth of cells can lead to the development of a tumor. A similar outcome may result from inappropriate repression of a gene that normally suppresses cellular proliferation.

Less than five years ago, an entirely new mechanism of regulating the level of activity of a gene was discovered. This new regulatory pathway relies on tiny molecules called microRNAs which, when produced by a cell, are able to turn off specific sets of genes. It was subsequently shown that many different types of cancer cells produce abnormal amounts of microRNAs.

We discovered that a protein that is known to potently drive cellular proliferation and tumorigenesis activates expression of a specific group of microRNAs. These findings provide insight into the mechanisms that regulate microRNA expression in normal cells and cancer cells.

Some of the earliest microRNAs that were discovered in model organisms were found to regulate processes such as cellular differentiation, proliferation, and death. Since abnormalities in these processes are also fundamental to the development of cancer, we speculated that microRNAs might be dysregulated in this disease.

To test this hypothesis, we developed methodologies to gloabally monitor microRNA expression profiles. As we began using these systems, we realized that microRNAs might also be directly regulated by oncogenes during neoplastic transformation. This led us to begin experimenting with c-Myc.