Study Identifies Novel Highlights for Sarcoma Research

The study, “Lost miRNA surveillance of Notch, IGFR pathway — road to sarcomagenesis,” was published in the January issue of Tumor Biology, the official journal of the International Society of Oncology and BioMarkers.

Sarcomas are a group that makes up more than 60 different tumors that affect bone and connective tissues. Chondrosarcomas are the second most common bone malignancy and do not respond to conventional therapy.

Together with H. Thomas Temple, M.D., professor and Vice Chair of Orthopedics and Director of the Tissue Bank, who in 2010 established the Musculoskeletal Oncology Signal Transduction Laboratory to investigate the molecular pathways leading to metastatic sarcomas, Galoian and her team compared and analyzed differentially expressed miRNA and their targets in chondrosarcoma versus control chondrocytes.

“Under normal conditions, mesenchymal cells support and produce a matrix for connective tissues; however, the signaling events resulting in mesenchymal cell transformation to sarcoma are not known,” said Temple, who is senior author of the study. “Understanding the molecular basis of the disease is critical to developing effective targeted therapies.”

The study included 148 upregulated and 188 downregulated miRNAs from 3,045 targets. The majority of downregulated miRNAs were oncosuppressors, whereas the upregulated miRNAs were linked to promotion of an aggressive phenotype. For example, miRNA 551a was upregulated 73.69-fold, and miRNA 886-3p, the RNA component of the ribonucleoprotein called vault, was downregulated 218-fold.

Among downregulated targets were claudins (CLDN1), a family of proteins that form tight junctions that act as tumor suppressors in normal tissues. Among upregulated targets were the cluster of cancer testis antigens (CTA) genes, located on chromosome X. Their expression correlated to IGFR pathway activity, suggesting that massive (more than 100-fold) upregulation of CTA genes in chondrosarcoma is due to hypomethylation under control of epi-miRNAs, a specific group of miRNAs that affect the expression of tumor suppressor genes.

“Our study shows that lost miRNA surveillance of notch signaling and IGFR pathways is involved in and possibly leads to sarcomagenesis,” said Galoian, first author of the study. “We believe that upregulated miRNAS, which target CTA genes, are epi-miRNAs that influence target gene expression by directly regulating epigenetic processes. We must investigate the processes that alter noncoding RNA transcripts and miRNAs, because the genomic complexity of cancer is far greater than expected.”

Galoian says future studies will focus on the mechanisms and reasons leading to the deranged surveillance of miRNA as a result of aberrant expression or erratic miRNA processing during malignancy.

The results also were presented at the November 2 Connective Tissue Oncology Society meeting in New York City.

In addition to Galoian and Temple, other co-authors include Biju Issac, Ph.D., associate scientist in the Division of Bioinformatics at Sylvester Comprehensive Cancer Center, Loida Navarro, research associate in the Oncogenomics Core at Sylvester, and Toumy Guettouche, Ph.D., senior scientist and Director of Sequencing at the Children’s Hospital of Philadelphia.

The project was funded by the University of Miami Tissue Bank and the Miami CORE (Center for Orthopaedic Research and Education), which is directed by Mark D. Brown, M.D., Ph.D., professor of orthopaedics.

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