miRNA signatures in childhood sarcomas and their clinical implications

Viera, G. M.; Salomão, Karina Bezerra; Sousa, Graziella Ribeiro de; Baroni, Mirella; Delsin, Lara Elis Alberici; Pezuk, Julia Alejandra; Brassesco, María Sol

doi:10.1007/s12094-019-02104-z

Cited by 13 publications

(10 citation statements)

References 607 publications

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“…Emerging evidence suggests that miRNAs can function as tumor suppressors or oncogenes depending on their target mRNAs, thereby markedly affecting the biology of cancer. [19][20][21] Several miRNAs have been identified as being associated with different cancers, including OS, 22,23 and there is evidence that miR-193b acts as a tumor suppressor in various types of cancer. [24][25][26][27][28][29][30] In the present study, we demonstrated that miR-193b expression is lower in OS specimens than in adjacent normal tissue.…”

Section: Discussionmentioning

confidence: 99%

<p>miR-193b Increases the Chemosensitivity of Osteosarcoma Cells by Promoting FEN1-Mediated Autophagy</p>

Dong¹,

Ye²,

Ma³

et al. 2019

OTT

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Background: Osteosarcoma (OS) is one of the most common malignant bone tumors and specific microRNAs (miRNAs) are closely associated with malignant OS progression. In this study, we examined the role of and the involvement of autophagy and apoptosis in the chemosensitivity of OS cells. Methods: We employed qRT-PCR, Western blot, and immunohistochemistry to examine the expression levels of miR-193b, flap endonuclease 1 (FEN1), and autophagy-related proteins. Apoptosis was determined by flow cytometry using an Annexin V-FITC/PI apoptosis detection kit. Luciferase reporter assays confirmed the relationship between miR-193b and FEN1. Results: miR-193b was downregulated in OS compared to adjacent normal tissues (p < 0.05). miR-193b overexpression in the OS cell lines induced autophagy and apoptosis, as shown by Western blotting and flow cytometry. Knockdown of FEN1, a structure-specific nuclease overexpressed in OS tissues (p < 0.001), induced apoptosis through activation of autophagy. Luciferase reporter assays confirmed that FEN1 is a direct target of miR-193b, FEN1 knockdown reinforced miR-193b induced apoptosis. Moreover, miR-193b expression enhanced epirubicin-induced autophagy and apoptosis. Conclusion: Collectively, the results showed that miR-193b/FEN1 may serve as a novel therapeutic target for OS aimed mainly at the induction of autophagy and apoptosis. The miR-193b/FEN1 axis increased the chemosensitivity of OS cells, while activation of autophagy enhanced the anticancer effects of epirubicin.

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Section: Discussionmentioning

confidence: 99%

<p>miR-193b Increases the Chemosensitivity of Osteosarcoma Cells by Promoting FEN1-Mediated Autophagy</p>

Dong¹,

Ye²,

Ma³

et al. 2019

OTT

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“…Several studies have shown that ESFT tumor cells contain unique miRNA profiles. 32 - 35 We found this to also be true for ESFT derived sEVs; however, we were surprised by the enrichment of miRNA within correlative ESFT-derived sEVs. In this work we show for the first time that ESFT sEVs contain an increased level and number of individual miRNAs as compared to controls.…”

Section: Discussionmentioning

confidence: 74%

MicroRNA Content of Ewing Sarcoma Derived Extracellular Vesicles Leads to Biomarker Potential and Identification of a Previously Undocumented EWS-FLI1 Translocation

et al. 2022

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Objective: Ewing Sarcoma Family of Tumors (ESFT) are a highly aggressive pediatric bone and soft tissue malignancy with poor outcomes in the refractory and recurrent setting. Over 90% of Ewing Sarcoma (ES) tumors are driven by the pathognomonic EWS-ETS chimeric transcripts and their corresponding oncoproteins. It has been suggested that the EWS-ETS oncogenic action can mediate microRNA (miRNA) processing. Importantly, small extracellular vesicles (sEVs), including those frequently referred to as exosomes have been shown to be highly enriched with tumor-derived small RNAs such as miRNAs. We hypothesized that ESFT-specific sEVs are enriched with certain miRNAs which could be utilized toward an exo-miRNA biomarker signature specific to this disease. Methods: We performed miRNAseq to compare both the exo-derived and cell-derived miRNA content from 8 ESFT, 2 osteosarcoma, 2 non-cancerous cell lines, and pediatric plasma samples. Results: We found that sEVs derived from ESFT cells contained nearly 2-fold more number of unique individual miRNAs as compared to non-ESFT samples. Quantitative analysis of the differential enrichment of sEV miRNAs resulted in the identification of 62 sEV-miRNAs (exo-miRNAs) with significant ( P < .05) enrichment variation between ESFT and non-ESFT sEV samples. To determine if we could utilize this miRNA signature to diagnose ESFT patients via a liquid biopsy, we analyzed the RNA content of total circulating sEVs isolated from 500 µL plasma from 5 pediatric ESFT patients, 2 pediatric osteosarcoma patients, 2 pediatric rhabdomyosarcoma patients, and 4 non-cancer pediatric controls. Pearson’s clustering of 60 of the 62 candidate exo-miRNAs correctly identified 80% (4 of 5) of pathology confirmed ESFT patients. Importantly, RNAseq analysis of tumor tissue from the 1 outlier, revealed a previously uncharacterized EWS-FLI1 translocation.Conclusions: Taken together, these findings support the development and validation of an exo-miRNA-based liquid biopsy to aid in the diagnosis and monitoring of ESFT.

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“…Many studies reflect the important role that miRNAs play in the molecular regulation, the appearance and the progression of human OS. Some of these miRNAs act as tumor suppressors, whilst others act as oncogenes [ 61 ]. Different miRNAs will act on a diverse range of molecular targets and pathways.…”

Section: Micrornas: Biogenesis and Biological Functionsmentioning

confidence: 99%

Role of MicroRNAs in Human Osteosarcoma: Future Perspectives

Llobat

Gourbault²

2021

Biomedicines

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Osteosarcoma (OS) is a rare form of cancer with high death rate but is one of the most frequent forms of bone cancer in children and adolescents. MiRNAs are small endogenous RNAs that regulate gene expression post-transcriptionally. The discovery of miRNAs could allow us to obtain an earlier diagnosis, predict prognosis and chemoresistance, and lead to the discovery of new treatments in different types of tumors, including OS. Despite the fact that there is currently only one clinical trial being carried out on a single miRNA for solid tumors, it is very probable that the number of clinical trials including miRNAs as prognostic and diagnostic biomarkers, as well as potential therapeutic targets, will increase in the near future. This review summarizes the different miRNAs related to OS and their possible therapeutic application.

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miRNA signatures in childhood sarcomas and their clinical implications

Cited by 13 publications

References 607 publications

<p>miR-193b Increases the Chemosensitivity of Osteosarcoma Cells by Promoting FEN1-Mediated Autophagy</p>

<p>miR-193b Increases the Chemosensitivity of Osteosarcoma Cells by Promoting FEN1-Mediated Autophagy</p>

MicroRNA Content of Ewing Sarcoma Derived Extracellular Vesicles Leads to Biomarker Potential and Identification of a Previously Undocumented EWS-FLI1 Translocation

Role of MicroRNAs in Human Osteosarcoma: Future Perspectives

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