miR-34a predicts survival of Ewing's sarcoma patients and directly influences cell chemo-sensitivity and malignancy

Fumihiko Nakatani, Manuela Ferracin, Maria Cristina Manara, Selena Ventura, Valentina Del Monaco, Stefano Ferrari, Marco Alberghini, Andrea Grilli, Sakari Knuutila, Karl Ludwig Schaefer, Gianfranco Mattia, Massimo Negrini, Piero Picci, Massimo Serra, Katia Scotlandi

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Abstract

Identification of factors to detect chemotherapy-resistant tumours at diagnosis is a first priority for risk-adapted therapy in the oncology of children and young adults, where more individualized, effective, and less toxic treatments are highly desirable. In this study, we analysed the miRNAs discriminating Ewing's sarcoma (EWS) patients with different clinical outcomes in order to identify new indicators of prognosis. miRNA expression was investigated in 49 primary EWSs by using the Agilent human miRNA microarray v.2 and/or qRT-PCR. Statistical power of the samples studied for miRNA expression was verified, indicating adequate sample size. Microarray analysis defined a signature of five miRNAs (miR-34a, miR-23a, miR-92a, miR-490-3p, and miR-130b) as an independent predictor of risk for disease progression and survival. Validation analysis in the extended sample set indicated that both miR-34a and miR-490-3p achieved sufficient statistical power to predict prognosis. Results were particularly robust for miR-34a, which appeared associated with either event-free or overall survival and emerged as a significant predictor also after multivariate analysis. Patients with the highest expression of miR-34a did not experience adverse events in 5 years; in contrast, patients with the lowest expression recurred within 2 years. High expression of miR34a can be detected also in paraffin-embedded tissues by in situ hybridization, thus contributing to an easy routine evaluation of this miRNA. Functional analysis of miR-34a in EWS cell lines indicated that when miR-34a expression was enforced, cells were less proliferative, less malignant, and sensitized to doxorubicin and vincristine. Expression of miR-34a could be increased in p53wt cells by treatment with nutlin-3a. Accordingly, nutlin-3a synergizes with doxorubicin. Overall, our data indicate that miR-34a expression is a strong predictor of outcome in EWS. Restoration of miR-34a activity may be useful to decrease malignancy and increase tumour sensitivity to current drugs, so sparing excessive long-term toxicity to EWS patients.

Original languageEnglish
Pages (from-to)796-805
Number of pages10
JournalJournal of Pathology
Volume226
Issue number5
DOIs
Publication statusPublished - Apr 2012

Fingerprint

Ewing's Sarcoma
MicroRNAs
Survival
Neoplasms
Doxorubicin
Poisons
Vincristine
Microarray Analysis
Paraffin
Sample Size
In Situ Hybridization
Disease Progression
Young Adult
Therapeutics
Multivariate Analysis
Drug Therapy
Cell Line
Polymerase Chain Reaction
Pharmaceutical Preparations

Keywords

  • Ewing's sarcoma
  • miR-34a
  • miRNAs
  • p53
  • Prognostic biomarkers

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

miR-34a predicts survival of Ewing's sarcoma patients and directly influences cell chemo-sensitivity and malignancy. / Nakatani, Fumihiko; Ferracin, Manuela; Manara, Maria Cristina; Ventura, Selena; Del Monaco, Valentina; Ferrari, Stefano; Alberghini, Marco; Grilli, Andrea; Knuutila, Sakari; Schaefer, Karl Ludwig; Mattia, Gianfranco; Negrini, Massimo; Picci, Piero; Serra, Massimo; Scotlandi, Katia.

In: Journal of Pathology, Vol. 226, No. 5, 04.2012, p. 796-805.

Research output: Contribution to journalArticle

Nakatani, F, Ferracin, M, Manara, MC, Ventura, S, Del Monaco, V, Ferrari, S, Alberghini, M, Grilli, A, Knuutila, S, Schaefer, KL, Mattia, G, Negrini, M, Picci, P, Serra, M & Scotlandi, K 2012, 'miR-34a predicts survival of Ewing's sarcoma patients and directly influences cell chemo-sensitivity and malignancy', Journal of Pathology, vol. 226, no. 5, pp. 796-805. https://doi.org/10.1002/path.3007
Nakatani, Fumihiko ; Ferracin, Manuela ; Manara, Maria Cristina ; Ventura, Selena ; Del Monaco, Valentina ; Ferrari, Stefano ; Alberghini, Marco ; Grilli, Andrea ; Knuutila, Sakari ; Schaefer, Karl Ludwig ; Mattia, Gianfranco ; Negrini, Massimo ; Picci, Piero ; Serra, Massimo ; Scotlandi, Katia. / miR-34a predicts survival of Ewing's sarcoma patients and directly influences cell chemo-sensitivity and malignancy. In: Journal of Pathology. 2012 ; Vol. 226, No. 5. pp. 796-805.
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AU - Ventura, Selena

AU - Del Monaco, Valentina

AU - Ferrari, Stefano

AU - Alberghini, Marco

AU - Grilli, Andrea

AU - Knuutila, Sakari

AU - Schaefer, Karl Ludwig

AU - Mattia, Gianfranco

AU - Negrini, Massimo

AU - Picci, Piero

AU - Serra, Massimo

AU - Scotlandi, Katia

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N2 - Identification of factors to detect chemotherapy-resistant tumours at diagnosis is a first priority for risk-adapted therapy in the oncology of children and young adults, where more individualized, effective, and less toxic treatments are highly desirable. In this study, we analysed the miRNAs discriminating Ewing's sarcoma (EWS) patients with different clinical outcomes in order to identify new indicators of prognosis. miRNA expression was investigated in 49 primary EWSs by using the Agilent human miRNA microarray v.2 and/or qRT-PCR. Statistical power of the samples studied for miRNA expression was verified, indicating adequate sample size. Microarray analysis defined a signature of five miRNAs (miR-34a, miR-23a, miR-92a, miR-490-3p, and miR-130b) as an independent predictor of risk for disease progression and survival. Validation analysis in the extended sample set indicated that both miR-34a and miR-490-3p achieved sufficient statistical power to predict prognosis. Results were particularly robust for miR-34a, which appeared associated with either event-free or overall survival and emerged as a significant predictor also after multivariate analysis. Patients with the highest expression of miR-34a did not experience adverse events in 5 years; in contrast, patients with the lowest expression recurred within 2 years. High expression of miR34a can be detected also in paraffin-embedded tissues by in situ hybridization, thus contributing to an easy routine evaluation of this miRNA. Functional analysis of miR-34a in EWS cell lines indicated that when miR-34a expression was enforced, cells were less proliferative, less malignant, and sensitized to doxorubicin and vincristine. Expression of miR-34a could be increased in p53wt cells by treatment with nutlin-3a. Accordingly, nutlin-3a synergizes with doxorubicin. Overall, our data indicate that miR-34a expression is a strong predictor of outcome in EWS. Restoration of miR-34a activity may be useful to decrease malignancy and increase tumour sensitivity to current drugs, so sparing excessive long-term toxicity to EWS patients.

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