Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Scripps Research Institute Study Shows MicroRNAs Can Trigger Lymphomas

A small group of immune-regulating molecules, when overproduced even moderately, can trigger the blood cancers known as lymphomas, according to a new study led by scientists from The Scripps Research Institute (TSRI).

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.

‘Dimmer Switches’

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

The 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).

About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see
For information:
Office of Communications
Tel: 858-784-2666
Fax: 858-784-8136

Mika Ono | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>