A systems biology approach to characterize the regulatory networks leading to trabectedin resistance in an in vitro model of myxoid liposarcoma
| العنوان: | A systems biology approach to characterize the regulatory networks leading to trabectedin resistance in an in vitro model of myxoid liposarcoma |
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| المؤلفون: | Sergio Marchini, Chiara Romualdi, Duccio Cavalieri, Giovanna Chiorino, Paola Ostano, Eugenio Erba, Ilaria Fuso Nerini, Luca Beltrame, Sarah Uboldi, Daniela D'Angelo, Maurizio D'Incalci, Enrica Calura |
| المصدر: | PLoS ONE PLoS ONE, Vol 7, Iss 4, p e35423 (2012) |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Identification, systems biology, cancer, anti-tumor compound, sarcoma, trabectedin, miRNA, gene expression, regulatory network, Transcription, Genetic, Microarrays, Cancer Treatment, lcsh:Medicine, Expression, Fusion gene, Tetrahydroisoquinolines, Bone and Soft Tissue Sarcomas, lcsh:Science, Trabectedin, Genetics, Regulation of gene expression, Multidisciplinary, ABL, Systems Biology, Genomics, Cell cycle, Phase II, Liposarcoma, Myxoid, Neoplasm Proteins, Oncology, Medicine, Mechanism, medicine.drug, Research Article, Cells, Ecteinascidin-743, Dioxoles, Biology, Liposarcoma, Ovarian cancer, Cell Line, Tumor, medicine, Humans, RNA, Messenger, Antineoplastic Agents, Alkylating, Platinum, Regulatory Networks, Myxoid liposarcoma, Gene Expression Profiling, lcsh:R, Computational Biology, Cancers and Neoplasms, ET-743, Chemotherapy and Drug Treatment, medicine.disease, Gene expression profiling, MicroRNAs, Genes, Drug Resistance, Neoplasm, Cancer research, lcsh:Q, Genome Expression Analysis |
| الوصف: | 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. |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e85c89525ec0593aa162935fc3293f3cTest http://hdl.handle.net/2158/650728Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e85c89525ec0593aa162935fc3293f3c |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |