Scientists uncover previously hidden network that regulates cancer genes

October 18, 2011
Net One

The gene regulatory network in mammalian cells affects how tumors develop and grow (credit: Columbia University Medical Center)

Researchers at Columbia University Medical Center (CUMC) and two other institutions have uncovered a vast gene regulatory network (“mPR network“) in mammalian cells that could explain why there is such genetic variability in cancer.

The researchers say the findings could broaden inquiry into how tumors develop and grow, who is at risk for cancer, and even inactivate key cancer molecules.

“The discovery of this regulatory network fills in a missing piece in the puzzle of cell regulation and allows us to identify genes never before associated with a particular type of tumor or disease,” said Andrea Califano, professor of systems biology and director of the Columbia Initiative in Systems Biology.

For decades, scientists have thought that the primary role of messenger RNA (mRNA) is to shuttle information from the DNA to the ribosomes, the sites of protein synthesis. The new studies suggest that the mRNA of one gene can control, and be controlled by, the messenger RNA (mRNA) of other genes via a large pool of microRNA molecules, with dozens to hundreds of genes working together in complex self-regulating subnetworks.

For example, deletions of mRNA network regulators in the phosphatase and tensin homolog gene (PTEN), a major tumor suppressor, appear to be as damaging as mutations of the gene itself in several types of cancer, the studies show.

mPR network

The newly identified regulatory network (called the mPR network by the CUMC investigators) allows mRNAs to communicate through small bits of RNA called microRNAs. Researchers first realized about a decade ago that microRNAs, by binding to complementary genetic sequences on mRNAs, can prevent those mRNAs from making proteins. Turning this concept on end, the new studies reveal that mRNAs actually use microRNAs to influence the expression of other genes.

When two genes share a set of microRNA regulators, changes in expression of one gene affect the other. If, for instance, one of those genes is highly expressed, the increase in its mRNA molecules will “sponge up” more of the available microRNAs.

The researchers said this is the first time the range and relevance of this kind of interaction has been characterized.

In the CUMC study, Pavel Sumazin, research scientist in systems biology, and colleagues analyzed glioblastoma mRNA and microRNA expression data from the Cancer Genome Atlas, a public database, uncovering a regulatory layer comprising more than 248,000 microRNA-mediated interactions

The researchers found that the tumor suppressor gene PTEN is part of a subnetwork of more than 500 genes. Of these genes, 13 are frequently deleted in glioblastoma and seem to work together through microRNAs to stop PTEN activity — achieving the same result as if the tumors had inactivating mutations or deletions of PTEN itself.

The finding explains, at least in part, why all patients with glioblastoma do not share the same genetic profile. In about 80 percent of patients, their tumors have a deletion of PTEN. In most of the remaining 20 percent, PTEN is intact, but the gene is not expressed — an observation that had confounded researchers.

“This suggested that there must be some other mechanism by which PTEN can be completely suppressed,” said. Sumazin. “Now we know that there are at least 13 other genes — none of which had ever been implicated in cancer — that can ‘gang up’ on PTEN to suppress its activity, with different combination of deletions in different patients.

“The network helps explain the so-called dark matter of the genome. For years, scientists have been cataloging all the genes involved in particular diseases. But if you add up all the genetic and epigenetic alterations that have been identified, even with high-resolution studies, there are still many cases where you cannot explain why a person has the disease. Now we have a new tool for explaining these genetic variations, for gaining a better understanding of the disease and, ultimately, for finding new treatments.”

Ref.: Pavel Sumazin, et al., An Extensive MicroRNA-Mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in Glioblastoma, Cell, 2011; [DOI: 10.1016/j.cell.2011.09.041]