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 tumor promoter, but we don't know why it is upregulated in many cancers," says principal investigator Denis Guttridge, PhD, 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 says. "It also identifies NF-kB as a therapeutic target in sarcoma and A20 and miR-29 as potential biomarkers for sarcoma."
First author Mumtaz Yaseen Balkhi, PhD, notes that the findings move research a step closer toward developing miR-29 therapy against NF-kB activation in cancers. "A number of labs have tried to block NF-kB signaling using pharmacological inhibitors because of the perceived benefits for cancer treatment," Balkhi says. "We provide an alternative route, showing that microRNA can do the same job by acting as a decoy."
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, also sees the potential for developing novel therapies."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."
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.
The significant role played by the RNA binding protein HuR surprised the researchers. "This protein in tumors can destabilize the A20 tumor suppressor," Balkhi says. "The rescue of destabilized tumor suppressors that are unaffected by mutations is an attractive possibility in cancer research, and our results provide an important breakthrough in that direction."
Funding from the NIH/National Cancer Institute (grants CA163995-01, CA143082) and a Pelotonia fellowship supported this research.
- M. Yaseen Balkhi, O. H. Iwenofu, N. Bakkar, K. J. Ladner, D. S. Chandler, P. J. Houghton, C. A. London, W. Kraybill, D. Perrotti, C. M. Croce, C. Keller, D. C. Guttridge. miR-29 Acts as a Decoy in Sarcomas to Protect the Tumor Suppressor A20 mRNA from Degradation by HuR. Science Signaling, 2013; 6 (286): ra63 DOI: 10.1126/scisignal.2004177
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