Sarcoma Suppressor

Loss of MicroRNA Decoy Might Contribute to Development of Soft-Tissue Sarcoma

Denis GuttridgeOSUCCC – James researchers have discovered a novel mechanism responsible for the loss of a critical tumor-suppressor gene in rhabdomyosarcoma and other soft-tissue sarcomas. These rare cancers strike mainly children and often respond poorly to treatment; their cause is largely unknown. The discovery of the mechanism could lead to more effective therapies for these malignancies, 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.

Guttridge and his colleagues found that the tumor-suppressor gene called A20 is silenced not by mutation but because a second molecule is lost, a small molecule called microRNA-29 (miR-29). They also 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 NFkB and to tumor progression.

“NF-kB is a known tumor promoter, but we don’t know why it is upregulated in many cancers,” Guttridge says. The findings identify 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 closer to developing miR-29 therapy against NF-kB activation. “Other labs have tried to block NF-kB signaling using pharmacological inhibitors because of the perceived benefits for cancer treatment,” he says. “We provide an alternative route, showing that microRNA can do the same job by acting as a decoy.”

“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. Soft-tissue sarcomas make up about 15 percent of pediatric cancer cases. In 2013, about 11,400 cases of sarcoma were expected in the United States, and about 4,400 Americans were expected to die from the malignancy.

Published in the journal Science Signaling.

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