Researchersat The Ohio State University Comprehensive Cancer Center ? Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC ? James)have discovered a novel mechanism responsible for the loss of a critical tumor-suppressor gene in rhabdomyosarcoma and other soft-tissue sarcomas.


We are excited about these findings because they open up new vistas on the role of microRNAs in sarcoma…


Soft-tissue sarcomas ? cancers of muscle, other soft tissues and bone ? arerare cancers that strike mainly children and often respond poorly to treatment. These sarcomasmake up about 15% 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.Their cause is largely unknown.

Better understanding
According to the researchers, a better understanding of themolecular events – the underlying mechanism – at the root of these malignancies may guide the development of more effective therapies for these malignancies.

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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.

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The findings of the researchers are published in the journal july 23, 2013 issue ofScience Signaling.

?We do know that NF-kB is a tumor promoter, but we don’t know why it is upregulated in many cancers,? noted principal investigator Denis Guttridge, PhD, (Photo 1) professor of molecular virology, immunology and medical genetics 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 continued. ?It also identifies NF-kB as a therapeutic target 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,? observed O. Hans Iwenofu, MD, FCAP, assistant professor of pathology and co-author of the study.

Key Findings
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 explained.

For more information:
Yaseen Balkhi M, Iwenofu OH, Bakkar N, Ladner KJ, Chandler DS, Houghton PJ, London CA, et al. miR-29 Acts as a Decoy in Sarcomas to Protect the Tumor Suppressor A20 mRNA from Degradation by HuR. Signal. 2013 Jul 30;6(286):ra63. doi: 10.1126/scisignal.2004177 [Abstract][PubMed]

Photo 1: Denis Guttridge, PhD; Photo 2: O. Hans Iwenofu, MD, FCAP.Photo Courtesy:The Ohio State University Comprehensive Cancer Center ? Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

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