The six “microRNA” molecules were already known to be overproduced in lymphomas and in many other human cancers, but no one had demonstrated that they can be the prime cause of such cancers—until now. The new study also identified the major biological pathways through which these microRNAs ignite and maintain cancerous growth.
“We were able to show how this microRNA cluster can be the main driver of cancer, and so we now can start to think about therapies to combat its effects,” said TSRI Assistant Professor Changchun Xiao. Xiao was the senior investigator for the study, which appeared this week in an advance online version of the EMBO Journal, a publication of the European Molecular Biology Organization.
Discovered only in the 1990s, microRNAs are short molecules that work within virtually all animal and plant cells. Typically each one functions as a “dimmer switch” for one or more genes; it binds to the transcripts of those genes and effectively keeps them from being translated into proteins. In this way microRNAs can regulate a wide variety of cellular processes.
The focus of the new study was a cluster of six microRNAs known as miR-17~92, encoded by a single gene on chromosome 13. Studies of miR-17~92, including one from Xiao’s lab earlier this year, have shown that it controls various immune-related and developmental processes, depending on the type of cell in which it is expressed.
But the miR-17~92 cluster is best known as a suspected cause of cancers, so much so that it has been dubbed “oncomir-1.” Since 2005, scientists have found the cluster to be overproduced in lymphomas, leukemias, brain cancers, breast cancers, prostate cancers and other tumor types. It appears to play an especially prominent role in lymphomas. In a study reported last year, National Cancer Institute researchers found a drastic overexpression of the miR-17~92 cluster in every tumor they sampled from patients with a common type of non-Hodgkin’s lymphoma called Burkitt lymphoma.
Researchers have found evidence that this overexpression of miR-17~92 isn’t merely an incidental result of cancerous change in cells; it also works to speed up cancerous growth. “What hasn’t been known is whether miR-17~92 can be the primary trigger of such cancers,” said Xiao.
Identifying a Primary Trigger for Cancer
In the new study, he and his colleagues demonstrated that it can be. The project started with a colony of genetically engineered mice that Xiao established several years ago, while doing postdoctoral research in the laboratory of renowned immunologist Klaus Rajewsky at Harvard Medical School. “The mice contain an artificial gene segment that we can activate to overproduce miR-17~92 in any chosen cell type,” explained Xiao. In this case, the overproduction occurs only in antibody-producing immune cells called B cells—the same cells from which Burkitt lymphoma originates.
After moving to TSRI to set up his own laboratory in 2008, Xiao expanded this transgenic mouse colony and began to gather data on it. “We found that 80 percent of these mice develop lymphomas within one year,” said Hyun-Yong Jin, a graduate student in the Xiao laboratory who was a lead author of the new study.
“It was striking that this very high rate of lymphoma came from only a three-to-fivefold overexpression of miR-17~92 in B cells, whereas human Burkitt lymphomas typically show more than tenfold overexpression,” Xiao said.
Having established that miR-17~92 overexpression can powerfully trigger B cell lymphomas, Xiao and his colleagues looked at this microRNA cluster’s role in a standard mouse model of Burkitt lymphoma. The B cells of these mice are engineered to overexpress a cancer-inducing “oncogene” called myc, whose hyperactivity—a characteristic of human Burkitt lymphoma cases—triggers a number of abnormalities, including the overproduction of miR-17~92.
The miR-17~92 overproduction turned out to be crucial for the development of these lymphomas. “Deleting miR-17~92 from the B cells of these mice significantly delayed the development of lymphomas and extended the mice’s survival,” said Maoyi Lai, a research associate in the Xiao laboratory who was a lead author of the study with Hiroyo Oda, a research associate in the Xiao laboratory during the study and now a member of the National Center for Global Health and Medicine in Chiba, Japan. “Looking more closely, we found that the lymphomas that did develop in these mice originated only from B cells in which miR-17~92 had managed to escape deletion and was still being overproduced.”
Taking Off the Brakes
The next step was to investigate how miR-17~92 triggers cancer so powerfully. Using a new technique for finding the binding sites of microRNAs on messenger RNAs, Xiao’s collaborator Bryan R. Cullen and colleagues at the Duke University School of Medicine identified hundreds of genes that miR-17~92 works to suppress. A large fraction of these turned out to be genes that normally keep the brakes on cell growth and survival programs. By suppressing these braking genes, miR-17~92 ends up strongly promoting cell growth and survival. “It affects so many important pathways that even a modest miR-17~92 overexpression apparently moves the cell from a normal growth and survival mode into the cancerous state,” Xiao said.
Xiao’s team demonstrated the importance of two of these growth/survival pathways by injecting chemical inhibitors of the pathways into mice with miR-17~92-driven lymphomas. “Each inhibitor shrank the tumors and prolonged mouse survival,” said Xiao. “We’re now studying the effect of combining inhibitors of these miR-17~92-driven cancer pathways and possibly targeting miR-17~92 microRNAs directly.”
Contributors to the study, “MicroRNA-17~92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways,” included Bryan R. Cullen and his postdoctoral fellow Rebecca L. Skalsky at Duke University School of Medicine; Klaus Rajewsky of Harvard Medical School (now at the Max Delbrück Center for Molecular Medicine in Berlin); Kelly Bethel of Scripps Clinic in La Jolla, CA, who performed the pathology studies of mouse lymphomas; and Jovan Shepherd, Seung Goo Kang, Wen-Hsien Liu and Mohsen Sabouri-Ghomi of the Xiao laboratory at TSRI. For more information on the paper, see http://www.nature.com/emboj/journal/vaop/ncurrent/full/emboj2013178a.htmlThe study was funded by the PEW Charitable Trusts, the Cancer Research Institute, and the National Institutes of Health (R01 AI067968, R01 AI087634 and RC1 CA146299).
Mika Ono | EurekAlert!
Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard
New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State University
A study carried out by an international team of researchers and published in the journal Physical Review X shows that ion-trap technologies available today are suitable for building large-scale quantum computers. The scientists introduce trapped-ion quantum error correction protocols that detect and correct processing errors.
In order to reach their full potential, today’s quantum computer prototypes have to meet specific criteria: First, they have to be made bigger, which means...
Since 2016, German and Spanish researchers, among them scientists from the University of Göttingen, have been hunting for exoplanets with the “Carmenes”...
DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.
Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...
MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.
Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...
Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...
11.12.2017 | Event News
08.12.2017 | Event News
07.12.2017 | Event News
18.12.2017 | Physics and Astronomy
18.12.2017 | Studies and Analyses
18.12.2017 | Medical Engineering