University Of Pennsylvania Researchers Find Role For MicroRNAs In Oxygenation, Nourishing Of Colon Tumors - RNA

University Of Pennsylvania Researchers Find Role For MicroRNAs In Oxygenation, Nourishing Of Colon Tumors
8/1/2006
Bioresearch Online
Philadelphia - Researchers from the University of Pennsylvania School of Veterinary Medicine have identified how molecules of microRNA are responsible for the growth of blood vessels in a model for human colon cancer. The process, called angiogenesis, results in ability of ravenous cancer cells to recruit blood vessels and receive a steady supply of nutrients and oxygen.
The findings, which appear in the online version of Nature Genetics, suggest that these microRNAs might also be a good target for future therapeutics designed to slow the growth of cancer cells.
"These findings also uncover a new role for a well-known cancer-causing gene called MYC," said Andrei Thomas-Tikhonenko, professor in Penn Vet's Department of Pathobiology. "We have discovered that, within a tumor cell, one of the tasks of MYC is to turn loose a particular set of microRNAs, which then becomes responsible for promoting the growth of new blood vessels that nourish the tumor."
MicroRNAs are, as the name implies, short strands of RNA. During the last few years, microRNAs have been found to have a significant role in the process by which genes are translated into proteins. Clusters of microRNA have been caught associated with messenger RNA, the intermediary molecule that "instructs" the cell's protein-building machinery. In particular, microRNAs help determine the life-span of messenger RNA and, therefore, how many copies of a protein can be made from a single messenger RNA molecule.
The Penn researchers discovered the role of microRNAs in angiogenesis while studying what makes MYC unique among other cancer-causing genes, or oncogenes. In particular, they were curious why cells with hyperactive MYC dont accumulate particularly fast in Petri dishes yet grow explosively in animal models for the disease
"There are obviously no blood vessels in a Petri dish, so the angiogenic properties of the MYC gene are not advantageous," said Michael Dews, senior researcher in the Thomas-Tikhonenko lab. "In the incubator, the cancer cells grow at normal rates, but in the mouse model you see them recruiting a lot of blood vessels and really taking off. Curiously, this is not the case with some other oncogenes. So, what makes MYC special?"
The MYC protein is known to have a role in determining how certain genes are transcribed into messenger RNAs. To understand the role of MYC in angiogenesis, the Penn researchers used microarray technology to screen MYC-positive and MYC-negative cancerous cells for the presence or absence of 192 known pro- and anti-angiogenesis molecules. They found that, while MYC did not lead to excessive amounts of pro-angiogenesis molecules, it did seem to depopulate an entire family of anti-angiogenesis molecules related to the so-called thrombospondin-1 protein. MYC effectively disabled the brakes that slow angiogenesis.
The Thomas-Tikhonenko lab had previously demonstrated that MYC decreases the lifespan of the messenger RNA encoding thrombospondin. Since microRNAs had emerged as important regulators of messenger RNA stability, the Penn researchers believed there was a good chance of a MYC-microRNA-thrombospondin connection.
Their long-standing collaborator Chi Dang, a professor at Johns Hopkins University, suggested talking to another Hopkins researcher, Joshua Mendell. Mendell had extensive expertise in microRNA function and just a few months ago teamed up with Dang to identify MYC as an important regulator of microRNAs. The new collaboration between the Thomas-Tikhonenko and Mendell laboratories identified a missing link between MYC and thrombospondin, which indeed turned out to be a microRNA cluster designated miR-17-92. In the key experiment the researchers engineered poorly angiogenic tumor cells to produce copious amounts of miR-17-92. These modified cells, just like cells with hyperactive MYC from earlier experiments, formed much larger tumors with better blood supplies.
"It has become increasingly clear that microRNAs are abnormally expressed in many types of cancer and select microRNAs have been demonstrated to act as a new type of oncogene," Mendell said. "As such, microRNAs represent an entirely new class of potential targets for cancer therapy."
According to Mendell, an "anti-sense" version of miR-17-92 could bind to miR-17-92, thereby canceling its effects. If it is possible to deliver regular miR-17-92 to increase angiogenesis, as was demonstrated in the Nature Genetics paper, it may be possible to deliver anti-sense miR-17-92 to decrease angiogenesis and tumor growth.
Researchers involved in this report include Asal Homayouni, Duonan Yu, and Cinzia Sevignani from the Penn School of Veterinary Medicine; Greg H. Enders, Emma E. Furth, William M. Lee and Danielle Murphy from Penn's School of Medicine; and Erik Wentzel from Johns Hopkins University.
Funding for this research was provided by the National Institutes of Health and a grant from the University of Pennsylvania Research Foundation.