A selective screening platform reveals unique global expression patterns of microRNAs in a cohort of human soft-tissue sarcomas

Abstract

Sarcomas are malignant heterogenous tumors of mesenchymal derivation. Emerging data suggest that miRNA might have a causal role in sarcomagenesis. Herein, we used a selective miRNA screening platform to study the comparative global miRNA expression signatures in a cohort of human sarcomas with the caveat that comparisons between tumor and non-tumor cells were performed from the same patients using formalin-fixed paraffin-embedded tissue. Five histologic types were examined that included: myxoid liposarcoma, well-differentiated liposarcoma, dedifferentiated liposarcoma, pleomorphic rhabdomyosarcoma, and synovial sarcoma. In addition, soft-tissue lipomas and normal fat were included as a separate set of controls for the lipogenic tumors. Clustering analysis showed a distinct global difference in expression patterns between the normal and sarcoma tissues. Expression signatures in an unsupervised hierarchical clustering analysis revealed tight clustering in synovial and myxoid liposarcomas, and the least clustering was observed in the pleomorphic rhabdomyosarcoma subtype. MiR-145 showed underexpression in pleomorphic rhabdomyosarcoma, well-differentiated liposarcoma, and synovial sarcoma. Unexpectedly, we found that a set of muscle-specific microRNAs (miRNAs; myomiRs): miR-133, miR-1, and miR-206 was significantly underexpressed in well-differentiated liposarcoma and synovial sarcoma, suggesting that they may function as tumor suppressors as described in muscle-relevant rhabdomyosarcomas. In addition, a tight linear progression of miRNA expression was identified from normal fat to dedifferentiated liposarcoma. These results suggest that miRNA expression profiles could elucidate classes of miRNAs that may elicit tumor-relevant activities in specific sarcoma subtypes. Sarcomas are rare malignant heterogeneous tumors of mesenchymal derivation with over 50 histologic types described. 1 The pathogenesis and biology of many of the different histologic subtypes remain poorly understood. Recent progress in understanding the biology of sarcomas has identified distinct molecular and pathologic entities within these heterogeneous groups of tumors that have paved the way for development of targeted therapies. There are emerging data that seem to suggest that miRNA might be a driver in sarcomagenesis with potential therapeutic implications. microRNAs (miRNAs) are non-coding strands of RNA of 22 nucleotides in length that regulate the expression of genes involved in processes such as development, differentiation, cell proliferation, metabolism, cell death, viral infection, and cancer. 2,3 They have a broad effect through base pairing with mRNA at their 3′ untranslated region to inhibit translation or to target the mRNA for degradation. Bioinformatics predictions have shown that miRNAs regulatẽ 30% of mammalian protein-coding genes. Their role in the molecular biology of cancers is well-established partly

Assessing the clinical value of microRNAs in formalin-fixed paraffin-embedded liposarcoma tissues: Overexpressed miR-155 is an indicator of poor prognosis

“…On the contrary, miR-143, miR-145 and miR-451, molecules with tumor suppressor properties in LPS [23, 35, 36], are clearly downregulated in LPS compared to LPM tissue specimens (Figure 2), corroborating the results of previously published studies [23, 24, 35, 36, 48, 50]. MiR-143 inhibits proliferation, induces apoptosis and cytokinesis of dedifferentiated liposarcoma cells by lowering BCL2 , TOP2A , PRC1 and PLK1 expression [36].…”

“…MiR-21 and miR-155 two of the most repeatedly reported upregulated miRNAs in LPS [23–26, 48] were also found to be robustly upregulated in our study and could efficiently discriminate LPS and LPM specimens with high specificity and sensitivity (Figure 2). Interestingly, a recent study by Boro et al showed that circulating levels of miRNA-155 in LPS patients correlate strongly with corresponding tissue levels.…”

Circulating MicroRNA-92b-3p as a Novel Biomarker for Monitoring of Synovial Sarcoma

“…To date, miRNA dysregulation in SS cells or tissue specimens has been reported by several groups (Supplementary Table S7 ) 13 – 18 . The representative functional miRNAs in SS cells includes the upregulated miR-17-5p 18 , miR-99b , miR-125a 15 , miR-183 17 , and the downregulated miR-143 16 .…”

The advancements of genomics and data integration in sarcoma research

“…Low expression of miR-145 in pleomorphic RMS, liposarcoma and synovial sarcoma was observed. Muscle-specific miR-133, miR-1 and miR-206 are expressed lower in liposarcoma and synovial sarcoma, indicating they may act as tumor suppressors in these tumors [78] . In addition, recent studies have employed qRT-PCR for osteosarcoma research.…”