MicroRNA signatures associate with pathogenesis and progression of osteosarcoma
A partir d'échantillons tumoraux prélevés sur des patients atteints d'un ostéosarcome, cette étude identifie une signature moléculaire, basée sur l'expression de plusieurs micro-ARNs, susceptible de servir de biomarqueur prédictif de la survenue de métastases et de la réponse thérapeutique
Osteosarcoma remains a leading cause of cancer death in adolescents, with no recent improvements in treatment or survival. Driving the lack of therapeutic inroads, the molecular etiology of osteosarcoma remains elusive. MicroRNAs (miRNAs) have demonstrated far-reaching effects on the cellular biology of development and cancer, but remain largely unexplored in osteosarcomagenesis. Here, we identify for the first time an miRNA signature reflecting the pathogenesis of osteosarcoma from surgically procured human specimens. The signature includes high expression of miR-181a, miR-181b, and miR-181c as well as reduced expression of miR-16, miR-29b, and miR-142-5p. We also demonstrate that miR-181b and miR-29b exhibit restricted expression to distinct cell populations in the tumor tissue. Further, higher expression of miR-27a and miR-181c* in pre-treatment biopsy samples characterized patients who developed clinical metastatic disease. In addition, higher expression of miR-451 and miR-15b in pre-treatment samples correlated with subsequent positive response to chemotherapy. In vitro and in vivo functional validation in osteosarcoma cell lines confirmed the tumor suppressive role of miR-16 and the pro-metastatic role of miR-27a. Furthermore, predicted target genes for miR-16 and miR-27a were confirmed as down-regulated by real-time PCR. Affymetrix array profiling of cDNAs from the osteosarcoma specimens and controls were interrogated according to predicted targets of miR-16, miR142-5p, miR-29b, miR-181a/b, and miR-27a. This analysis revealed positive and negative correlations highlighting pathways of known importance to osteosarcoma, as well as novel genes. Thus, our findings establish an miRNA signature associated with pathogenesis of osteosarcoma and critical pre-treatment biomarkers of metastasis and responsiveness to therapy.
Cancer Research , résumé, 2012