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

Mutant cells colonize our tissues over our lifetime

October 18, 2018
By the time we reach middle age, more than half of the oesophagus in healthy people has been taken over by cells carrying mutations in cancer genes, scientists have uncovered. By studying normal oesophagus tissue, scientists ...

Study involving hundreds of patient samples may reveal new treatment options of leukemia

October 17, 2018
After more than five years and 672 patient samples, an OHSU research team has published the largest cancer dataset of its kind for a form of leukemia. The study, "Functional Genomic Landscape of Acute Myeloid Leukemia", published ...

A 150-year-old drug might improve radiation therapy for cancer

October 17, 2018
A drug first identified 150 years ago and used as a smooth-muscle relaxant might make tumors more sensitive to radiation therapy, according to a recent study led by researchers at The Ohio State University Comprehensive Cancer ...

Loss of protein p53 helps cancer cells multiply in 'unfavourable' conditions

October 17, 2018
Researchers have discovered a novel consequence of loss of the tumour protein p53 that promotes cancer development, according to new findings in eLife.

Researcher fighting breast cancer with light therapy

October 17, 2018
When treatment is working for a patient who is fighting cancer, the light at the end of the tunnel is easier to see.

New method uses just a drop of blood to monitor lung cancer treatment

October 17, 2018
Dr. Tasuku Honjo won the 2018 Nobel Prize in physiology or medicine for discovering the immune T-cell protein PD-1. This discovery led to a set of anti-cancer medications called checkpoint inhibitors, one of the first of ...

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.