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Circulating miR34a levels as a potential biomarker in the follow-up of Ewing sarcoma

  • RESEARCH ARTICLE
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Journal of Cell Communication and Signaling Aims and scope

Abstract

Appropriate tools for monitoring sarcoma progression are still limited. The aim of the present study was to investigate the value of miR-34a-5p (miR34a) as a circulating biomarker to follow disease progression and measure the therapeutic response. Stable forced re-expression of miR34a in Ewing sarcoma (EWS) cells significantly limited tumor growth in mice. Absolute quantification of miR34a in the plasma of mice and 31 patients showed that high levels of this miRNA inversely correlated with tumor volume. In addition, miR34a expression was higher in the blood of localized EWS patients than in the blood of metastatic EWS patients. In 12 patients, we followed miR34a expression during preoperative chemotherapy. While there was no variation in the blood miR34a levels in metastatic patients at the time of diagnosis or after the last cycle of preoperative chemotherapy, there was an increase in the circulating miR34a levels in patients with localized tumors. The three patients with the highest fold-increase in the miR levels did not show evidence of metastasis. Although this analysis should be extended to a larger cohort of patients, these findings imply that detection of the miR34a levels in the blood of EWS patients may assist with the clinical management of EWS.

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Abbreviations

EWS:

Ewing sarcoma

miR34a:

miR-34a-5p

ctDNA:

circulating tumor DNA

FBS:

fetal bovine serum

STR:

short tandem repeat

GFP:

green fluorescence protein

pMIF-EV:

empty lentiviral vector

DXR:

doxorubicin

VCR:

vincristine

NSG:

NOD/SCID gamma

s.c.:

subcutaneously

IHC:

immunohistochemistry

ISH:

in situ miRNA hybridization

RT-qPCR:

quantitative reverse transcription PCR

ROC:

receiver operating characteristic

MRI:

magnetic resonance imaging

PRI:

EWS patients with localized primary tumors

PRI-Met:

EWS patients with detectable metastases at diagnosis

CTCs:

circulating tumor cells

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Acknowledgments

We are grateful to Chiara Gasperini, Michela Pierini, and Maria Teresa Marino for their technical support. We are indebted to Cristina Ghinelli for editing the manuscript.

Funding

This work was supported by the Italian Association for Cancer Research (AIRC project: IG18451 to KS) and by the PROVABES project (PER-2011-2353839). AD was awarded the AIRC fellowship “SITE” 19498.

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Author notes

  1. Marika Sciandra and Alessandra De Feo contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, via di Barbiano 1/10, 40136, Bologna, Italy

    Marika Sciandra, Alessandra De Feo, Alessandro Parra, Lorena Landuzzi, Maria Cristina Manara, Cristina Baricordi, Clara Guerzoni & Katia Scotlandi

  2. Department of Experimental, Diagnostic and Specialty Medicine, DIMES, University of Bologna, Bologna, Italy

    Pier-Luigi Lollini

  3. Oncology Unit, Center for Gender Medicine, Istituto Superiore di Sanità, Rome, Italy

    Gianfranco Mattia & Giada Pontecorvi

  4. Diagnostic and Interventional Radiology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy

    Alberto Bazzocchi

  5. Department of Chemotherapy, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy

    Alessandra Longhi

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  1. Marika Sciandra
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Contributions

MS, AD, and KS were responsible for the study design and critical revision of the manuscript. MS and AD were responsible for most of the experiments, data analysis, and figure preparation. CG, CB, MS and AD were responsible for the selection and characterization of the A673 transfected variants. LL and P-LL were responsible for the in vivo studies. AP and CB were responsible for plasma collection. MCM, MS and AD were responsible for IHC analysis. GM and GP were responsible for ISH analyses. AB and AL were responsible for updating patient clinical information and follow-up examinations. KS wrote the manuscript.

Corresponding authors

Correspondence to Alessandra De Feo or Katia Scotlandi.

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Conflict of interest

The authors declare that no conflicts of interest exist.

Ethics approval

The ethical committee of the Istituto Rizzoli approved the study involving human participants (0019012/2016 - AIRC 2016 and 0004340/2014 - PROVABES) and informed consent was obtained. The study was conducted in accordance with the Declaration of Helsinki ethical guidelines.

All animal procedures were done in accordance with European Directive 2010/63/UE and Italian law (DL 26/2014); experimental protocols were reviewed and approved by the institutional animal care and use committee (“Comitato per il Benessere Animale”) of the University of Bologna and by the Italian Ministry of Health with letters 782/2015-PR and 208/2017-PR.

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Sciandra, M., De Feo, A., Parra, A. et al. Circulating miR34a levels as a potential biomarker in the follow-up of Ewing sarcoma. J. Cell Commun. Signal. 14, 335–347 (2020). https://doi.org/10.1007/s12079-020-00567-2

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