Loss of MicroRNA Decoy Might Contribute to Development of Soft-Tissue Sarcoma
Researchers at 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, rare cancers that strike mainly children and often respond poorly to treatment. According to the study authors, knowledge of the mechanism could guide the development of more effective therapies for these malignancies. The findings were published in the journal Science Signaling.
The researchers found that the tumor-suppressor gene A20 is silenced not by mutation, as in many other cancers, but because a second molecule, microRNA-29 (miR-29), is lost. 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 NF-κB and to tumor progression.
“We do know that NF-κB is a tumor promoter, but we don't know why it is upregulated in many cancers,” said principal investigator Denis Guttridge, PhD, Professor of Molecular Virology, Immunology and Medical Genetics at OSUCCC – James.
“Our study indicates that it involves a regulatory circuit between NF-κB , miR-29, and the A20 tumor-suppressor gene,” Dr. Guttridge said. “It also identifies NF-κB 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,” said study pathologist and coauthor O. Hans Iwenofu, MD, FCAP, Assistant Professor of Pathology at OSUCCC.
Technical Findings
For this study, Drs. Guttridge and Iwenofu and 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-κB is constitutively active in sarcoma cancers,” Dr. Guttridge said.
The research was supported by funding from the NIH/National Cancer Institute (grants CA163995-01, CA143082) and a Pelotonia fellowship.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
