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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.

Loss of microRNA-29 (miR-29) and soft-tissue sarcomas in children

Soft-tissue sarcomas are rare cancers that mainly affect children and respond poorly to treatment. This study discovered molecular events that may help these malignancies develop, and could guide the design of new, more effective treatments.

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 this 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).

Researchers found that tumor-suppressor gene A20 is silenced (turned off) 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.”

“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:

(1) miR-29 and A20 expression are abnormally low in sarcomas;
(2) The A20 gene showed little evidence of mutation;
(3) Restoring miR-29 levels in sarcoma cells caused A20 levels to rise;
(4) miR-29 normally binds with a protein called HuR; when miR-29 is absent,
(5) HuR binds with A20, leading to the degradation of A20;
(6) When miR-29 binds with HuR, it acts as a decoy and protects A20 from HuR-mediated degradation.

Guttridge:“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.”

Abstract
In sarcoma, the activity of NF-B (nuclear factor B) reduces the abundance of the microRNA (miRNA) miR-29. The tumor suppressor A20 [also known as TNFAIP3 (tumor necrosis factor–α–induced protein 3)] inhibits an upstream activator of NF-B and is often mutated in lymphomas. In a panel of human sarcoma cell lines, we found that the activation of NF-B was increased and, although the abundance of A20 protein and mRNA was decreased, the gene encoding A20 was rarely mutated. The 3' untranslated region (UTR) of A20 mRNA has conserved binding sites for both of the miRNAs miR-29 and miR-125. Whereas the expression of miR-125 was increased in human sarcoma tissue, that of miR-29 was decreased in most samples. Overexpression of miR-125 decreased the abundance of A20 mRNA, whereas reconstituting miR-29 in sarcoma cell lines increased the abundance of A20 mRNA and protein. By interacting directly with the RNA binding protein HuR (human antigen R; also known as ELAVL1), miR-29 prevented HuR from binding to the A20 3'UTR and recruiting the RNA degradation complex RISC (RNA-induced silencing complex), suggesting that miR-29 can act as a decoy for HuR, thus protecting A20 transcripts. Decreased miR-29 and A20 abundance in sarcomas correlated with increased activity of NF-B and decreased expression of genes associated with differentiation. Together, the findings reveal a unique role of miR-29 and suggest that its absence may contribute to sarcoma tumorigenesis.

Funding from the NIH/National Cancer Institute (grants CA163995-01, CA143082) and a Pelotonia fellowship supported this research.

Other researchers involved in this study were Mumtaz Yaseen Balkhi, O. Hans Iwenofu, Katherine J. Ladner, Cheryl A. London, William Kraybill, Danilo Perrotti and Carlo M. Croce, The Ohio State University; Nadine Bakkar, Barrow Neurological Institute; Dawn S. Chandler, and Peter J. Houghton, Nationwide Children’s Hospital; Charles Keller, Oregon Health and Science University.

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State’s cancer program as “exceptional,” the highest rating given by NCI survey teams. As the cancer program’s 228-bed adult patient-care component, The James is a “Top Hospital” as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by U.S.News & World Report.

Original press release: http://cancer.osu.edu/mediaroom/releases/Pages/Loss-of-MicroRNA-Decoy-Might-Contribute-to-Development-of-Soft-Tissue-Sarcoma.aspx