Журнал канцерогенеза и мутагенеза

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Molecular Profiling of Human Primary Chondrosarcoma-Derived Spheres Reveals Specific and Target Genes Involved in Multidrug Resistance and Metastasis

Vincenzo Desiderio, Francesca Paino, Angela Nebbioso, Lucia Altucci, Giuseppe Pirozzi, Federica Papaccio, Marcella La Noce, Alfredo De Rosa, Gianpaolo Papaccio and Virginia Tirino

Chondrosarcoma is a malignant bone tumor that accounts for approximately 25% of all bone neoplasms. The “Cancer Stem Cell” (CSC) hypothesis states that tumor contains a cell subpopulation with stemness features. Sphere cultures are routinely used for self-renewal assays and to select CSCs. Our purpose was to investigate the gene profile of chondrospheres and identify target genes for chondrosarcoma treatment. Whole-genome microarray was used to compare the gene expression of floating spheres with that of adherent counterparts derived from a human primary chondrosarcoma. In addition, CD133, OCT4, SOX2, and collagen type II markers were tested both with Real-Time PCR and flow cytometry, and cell cycle analysis and resistance to cisplatin treatment were performed. Microarray analyses revealed that 1405 genes were found differentially expressed, of which 629 genes were upregulated and 776 down-regulated in chondrospheres, with a 2-fold cut-off threshold. Restricting analyses with a 3-fold cut-off threshold, the number of up-regulated and down-regulated probes was 251 and 302, respectively. The most highly up-regulated genes were involved in stemness, multidrug resistance, cell cycle, apoptosis regulation, migration, motility, and invasion. Furthermore, chondrospheres expressed CD133, OCT3/4, and SOX2, and showed a remarkable resistance to cisplatin-induced apoptosis compared with their adherent counterpart. In conclusion, this study highlights that: (i) the molecular profile of chondrospheres identifies genes that are potential targets for chondrosarcoma treatment and (ii) chondrospheres are strongly resistant to cisplatin treatment.