Prognostic microRNAs modulate the RHO adhesion pathway: A potential therapeutic target in undifferentiated pleomorphic sarcomas
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Philip Wong1,2,3, Angela Hui4, Jie Su5, Shijun Yue4, Benjamin Haibe-Kains4,12, Nalan Gokgoz6, Wei Xu5, Jeff Bruce4,12, Justin Williams4, Charles Catton1,2, Jay S. Wunder6,7,8, Irene L. Andrulis6,9,10, Rebecca Gladdy6,8, Brendan Dickson10,11, Brian O’Sullivan1,2 and Fei-Fei Liu1,2,4,12
1 Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
2 Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada
3 Département of Radiation Oncology, Centre Hospitalier de L’Université de Montréal, Montréal, QC, Canada
4 Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
5 Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON, Canada
6 The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
7 University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, ON, Canada
8 Department of Surgery, University of Toronto, Toronto, ON, Canada
9 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
10 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
11 Department of Pathology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
12 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
Fei-Fei Liu, email:
Keywords: biomarker, sarcoma, microRNA, prognostic, metastasis
Received: March 24, 2015 Accepted: April 08, 2015 Published: April 23, 2015
A common and aggressive subtype of soft-tissue sarcoma, undifferentiated pleomorphic sarcoma (UPS) was examined to determine the role of micro-RNAs (miRNAs) in modulating distant metastasis. Following histopathologic review, 110 fresh frozen clinically annotated UPS samples were divided into two independent cohorts for Training (42 patients), and Validation (68 patients) analyses. Global miRNA profiling on the Training Set and functional analysis in vitro suggested that miRNA-138 and its downstream RHO-ROCK cell adhesion pathway was a convergent target of miRNAs associated with the development of metastasis. A six-miRNA signature set prognostic of distant metastasis-free survival (DMFS) was developed from Training Set miRNA expression values. Using the six-miRNA signature, patients were successfully categorized into high- and low-risk groups for DMFS in an independent Validation Set, with a hazard ratio (HR) of 2.25 (p = 0.048). After adjusting for other known prognostic variables such as age, gender, tumor grade, size, depth, and treatment with radiotherapy, the six-miRNA signature retained prognostic value with a HR of 3.46 (p < 0.001). A prognostic miRNA biomarker for clinical validation was thus identified along with a functional pathway that modulates UPS metastatic phenotype.
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