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Prognostic microRNAs modulate the RHO adhesion pathway: A potential therapeutic target in undifferentiated pleomorphic sarcomas.

ABSTRACT: 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.

SUBMITTER: Wong P

PROVIDER: S-EPMC4770761 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Prognostic microRNAs modulate the RHO adhesion pathway: A potential therapeutic target in undifferentiated pleomorphic sarcomas.

Wong Philip P Hui Angela A Su Jie J Yue Shijun S Haibe-Kains Benjamin B Gokgoz Nalan N Xu Wei W Bruce Jeff J Williams Justin J Catton Charles C Wunder Jay S JS Andrulis Irene L IL Gladdy Rebecca R Dickson Brendan B O'Sullivan Brian B Liu Fei-Fei FF

Oncotarget 20151101 36

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 downstr ...[more]

PMID: 25970788

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Project description:Objective: Undifferentiated pleomorphic sarcoma (UPS) is a highly malignant, aggressive, and pleomorphic subtype of soft tissue sarcoma in adults. However, UPS is difficult to be diagnosed due to the lack of specific morphological and immunophenotypic features. Here, we aimed to identify new biomarkers for the diagnosis of UPS. Methods: The mRNA and protein expression of neurofibromin 1 (NF1) in 68 pairs of UPS and adjacent normal tissues were detected by qRT-PCR and immunohistochemistry, and the correlation between the NF1 protein expression and clinicopathological characteristics was analyzed. Then, differentially expressed microRNAs (DE miRNAs) were identified between the UPS tumor tissue and matched adjacent normal tissue using Hisep sequencing, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG). The DE miRNAs of the regulating NF1 gene were also identified using the TargetScan and miRanda databases and validated by qRT-PCR. Results: Compared with the adjacent normal tissue, both mRNA and protein expressions of NF1 in the UPS tumor tissue were significantly decreased, and the positive rate of NF1 protein was associated with the tumor size, metastasis, and recurrence. A total of 125 known DE miRNAs were identified from the screened miRNAs based on | log2(Fold Change) ≥5 and p-value < 0.05 (A total of 82 upregulated and 43 downregulated DE miRNAs in the UPS tissue). Target genes regulated by the DE miRNAs were enriched in pathways of metabolisms, RNA degradation, PI3K-Akt, and Rap1 pathway. In total, 11 miRNAs which were predicted to regulate the NF1 gene were screened. After verification, the relative expressions of hsa-miR-199a-3p and hsa-miR-34a-5p were increased and decreased in the UPS tumor tissue compared with those in the adjacent normal tissue, respectively. Conclusion: NF1 and NF1-related microRNAs including hsa-miR-199a-3p and hsa-miR-34a-5p may be novel biomarkers in the diagnosis of undifferentiated pleomorphic sarcoma (UPS).

Dataset Information

Prognostic microRNAs modulate the RHO adhesion pathway: A potential therapeutic target in undifferentiated pleomorphic sarcomas.

Publications

Prognostic microRNAs modulate the RHO adhesion pathway: A potential therapeutic target in undifferentiated pleomorphic sarcomas.

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