A systems biology approach to characterize the regulatory networks leading to trabectedin resistance in an in vitro model of myxoid liposarcoma

Sarah Uboldi, Enrica Calura, Luca Beltrame, Ilaria Nerini, Sergio Marchini, Duccio Cavalieri, Eugenio Erba, Giovanna Chiorino, Paola Ostano, Daniela D'Angelo, Maurizio D'Incalci, Chiara Romualdi

Research output: Contribution to journalArticle

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Abstract

Trabectedin, a new antitumor compound originally derived from a marine tunicate, is clinically effective in soft tissue sarcoma. The drug has shown a high selectivity for myxoid liposarcoma, characterized by the translocation t(12;16)(q13; p11) leading to the expression of FUS-CHOP fusion gene. Trabectedin appears to act interfering with mechanisms of transcription regulation. In particular, the transactivating activity of FUS-CHOP was found to be impaired by trabectedin treatment. Even after prolonged response resistance occurs and thus it is important to elucidate the mechanisms of resistance to trabectedin. To this end we developed and characterized a myxoid liposarcoma cell line resistant to trabectedin (402-91/ET), obtained by exposing the parental 402-91 cell line to stepwise increases in drug concentration. The aim of this study was to compare mRNAs, miRNAs and proteins profiles of 402-91 and 402-91/ET cells through a systems biology approach. We identified 3,083 genes, 47 miRNAs and 336 proteins differentially expressed between 402-91 and 402-91/ET cell lines. Interestingly three miRNAs among those differentially expressed, miR-130a, miR-21 and miR-7, harbored CHOP binding sites in their promoter region. We used computational approaches to integrate the three regulatory layers and to generate a molecular map describing the altered circuits in sensitive and resistant cell lines. By combining transcriptomic and proteomic data, we reconstructed two different networks, i.e. apoptosis and cell cycle regulation, that could play a key role in modulating trabectedin resistance. This approach highlights the central role of genes such as CCDN1, RB1, E2F4, TNF, CDKN1C and ABL1 in both pre- and post-transcriptional regulatory network. The validation of these results in in vivo models might be clinically relevant to stratify myxoid liposarcoma patients with different sensitivity to trabectedin treatment.

Original languageEnglish
Article numbere35423
JournalPLoS One
Volume7
Issue number4
DOIs
Publication statusPublished - Apr 16 2012

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trabectedin
Myxoid Liposarcoma
Systems Biology
cell lines
Biological Sciences
Cells
MicroRNAs
Cell Line
Genes
drugs
gene fusion
Tunicata
antineoplastic agents
sarcoma
resistance mechanisms
transcriptomics
proteomics
binding sites
cell cycle
genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A systems biology approach to characterize the regulatory networks leading to trabectedin resistance in an in vitro model of myxoid liposarcoma. / Uboldi, Sarah; Calura, Enrica; Beltrame, Luca; Nerini, Ilaria; Marchini, Sergio; Cavalieri, Duccio; Erba, Eugenio; Chiorino, Giovanna; Ostano, Paola; D'Angelo, Daniela; D'Incalci, Maurizio; Romualdi, Chiara.

In: PLoS One, Vol. 7, No. 4, e35423, 16.04.2012.

Research output: Contribution to journalArticle

Uboldi, Sarah ; Calura, Enrica ; Beltrame, Luca ; Nerini, Ilaria ; Marchini, Sergio ; Cavalieri, Duccio ; Erba, Eugenio ; Chiorino, Giovanna ; Ostano, Paola ; D'Angelo, Daniela ; D'Incalci, Maurizio ; Romualdi, Chiara. / A systems biology approach to characterize the regulatory networks leading to trabectedin resistance in an in vitro model of myxoid liposarcoma. In: PLoS One. 2012 ; Vol. 7, No. 4.
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AU - Marchini, Sergio

AU - Cavalieri, Duccio

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