title: A systems biology approach to characterize the regulatory networks leading to trabectedin resistance in an in vitro model of myxoid liposarcoma.
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.
authors.affiliation: Department of Oncology, Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Uboldi
authors.forename: Enrica
authors.initials: E
authors.lastname: Calura
authors.forename: Luca
authors.initials: L
authors.lastname: Beltrame
authors.forename: Ilaria
authors.initials: I
authors.lastname: Fuso Nerini
authors.forename: Sergio
authors.initials: S
authors.lastname: Marchini
authors.forename: Duccio
authors.initials: D
authors.lastname: Cavalieri
authors.forename: Eugenio
authors.initials: E
authors.lastname: Erba
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
authors.forename: Paola
authors.initials: P
authors.lastname: Ostano
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Angelo
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Chiara
authors.initials: C
authors.lastname: Romualdi
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004149:Dioxoles / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D018208:Liposarcoma, Myxoid / Q000188:drug therapy* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D049490:Systems Biology; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use*; D000077606:Trabectedin; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin