Loss of MicroRNA decoy might contribute to development of soft-tissue sarcoma

August 7, 2013, Ohio State University Medical Center

Researchers have discovered a novel mechanism responsible for the loss of a critical tumor-suppressor gene in rhabdomyosarcoma and other soft-tissue sarcomas, rare cancers that strike mainly children and often respond poorly to treatment. Their cause is largely unknown.

Knowledge of the mechanism could guide the development of more effective therapies for these malignancies, say researchers who led the study at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

The researchers found that the tumor-suppressor gene called A20 is silenced not by mutation, as in many other cancers, but because a second molecule is lost, a small molecule called microRNA-29 (miR-29). In addition, they found that miR-29 normally protects A20 from destruction. When miR-29 is absent, A20 is degraded. Loss of A20, in turn, leads to a dramatic rise in levels of a protein called NF-kB and to tumor progression.

The findings are published in the journal Science Signaling.

"We do know that NF-kB is a , but we don't know why it is upregulated in many cancers," says principal investigator Denis Guttridge, PhD, professor of , immunology and and a member of the OSUCCC – James Molecular Biology and Cancer Genetics Program.

"Our study indicates that it involves a regulatory circuit between NF-kB, miR-29 and the A20 tumor-suppressor gene," Guttridge says. "It also identifies NF-kB as a in sarcoma and A20 and miR-29 as potential biomarkers for sarcoma."

"We are excited about these findings because they open up new vistas on the role of microRNAs in sarcoma development and provide a rationale for further interrogating this circuitry as a potential target for new treatments," says study pathologist and coauthor O. Hans Iwenofu, MD, FCAP, assistant professor of pathology and member of the OSUCCC – James Molecular Biology and Cancer Genetics Program.

Soft-tissue sarcomas – cancers of muscle, other soft tissues and bone – make up about 15 percent of pediatric cancer cases. In 2013, about 11,400 cases of sarcoma are expected in the United States, and about 4,400 Americans are expected to die from the malignancy.

For this study, Guttridge, Iwenofu and their colleagues used human tumor samples, cell lines and animal models. Key technical findings include:

  • miR-29 and A20 expression are abnormally low in sarcomas;
  • The A20 gene showed little evidence of mutation;
  • Restoring miR-29 levels in sarcoma cells caused A20 levels to rise;
  • miR-29 normally binds with a protein called HuR; when miR-29 is absent, HuR binds with A20, leading to the degradation of A20;
  • When miR-29 binds with HuR, it acts as a decoy and protects A20 from HuR-mediated degradation.

"The loss of the A20 tumor-suppressor gene because the microRNA decoy is absent may represent another mechanism to explain why NF-kB is constitutively active in sarcoma cancers," Guttridge says.

Explore further: New point of focus found for the treatment of rheumatoid arthritis and other autoimmune diseases

More information: stke.sciencemag.org/cgi/conten … /sigtrans;6/286/ra63

Related Stories

New point of focus found for the treatment of rheumatoid arthritis and other autoimmune diseases

October 9, 2012
Scientists affiliated with VIB and UGent have discovered a mechanism used by the protein A20 to combat inflammation. This could be a very important point of focus in the search for a treatment for autoimmune diseases such ...

Researchers say one specific microrna promotes tumor growth and cancer spread

April 3, 2013
Researchers at Moffitt Cancer Center have determined that the overexpression of microRNA-155 (miR-155), a short, single strand of ribonucleic acid encoded by the miR-155 host gene, promotes the growth of blood vessels in ...

Defect in A20 gene expression causes rheumatoid arthritis

August 16, 2011
Researchers from VIB (Flanders Institute for Biotechnology) and Ghent University have shown that a defective gene can contribute to the onset of rheumatoid arthritis, an often-crippling inflammation of the joints that afflicts ...

Study identifies possible new acute leukemia marker, treatment target

May 13, 2013
A study has identified microRNA-155 as a new independent prognostic marker and treatment target in patients with acute myeloid leukemia that has normal-looking chromosomes under the microscope (that is, cytogenetically normal ...

Study reveals how normal cells fuel tumor growth

December 21, 2011
A new study published in the journal Nature Cell Biology has discovered how normal cells in tumors can fuel tumor growth.

Recommended for you

Study tracks evolutionary transition to destructive cancer

February 23, 2018
Evolution describes how all living forms cope with challenges in their environment, as they struggle to persevere against formidable odds. Mutation and selective pressure—cornerstones of Darwin's theory—are the means ...

Researchers use a molecular Trojan horse to deliver chemotherapeutic drug to cancer cells

February 23, 2018
A research team at the University of California, Riverside has discovered a way for chemotherapy drug paclitaxel to target migrating, or circulating, cancer cells, which are responsible for the development of tumor metastases.

Lab-grown 'mini tumours' could personalise cancer treatment

February 23, 2018
Testing cancer drugs on miniature replicas of a patient's tumour could help doctors tailor treatment, according to new research.

An under-the-radar immune cell shows potential in fight against cancer

February 23, 2018
One of the rarest of immune cells, unknown to scientists a decade ago, might prove to be a potent weapon in stopping cancer from spreading in the body, according to new research from the University of British Columbia.

Putting black skin cancer to sleep—for good

February 22, 2018
An international research team has succeeded in stopping the growth of malignant melanoma by reactivating a protective mechanism that prevents tumor cells from dividing. The team used chemical agents to block the enzymes ...

Cancer risk associated with key epigenetic changes occurring through normal aging process

February 22, 2018
Some scientists have hypothesized that tumor-promoting changes in cells during cancer development—particularly an epigenetic change involving DNA methylation—arise from rogue cells escaping a natural cell deterioration ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.