Micro RNAs, novel classifiers for human osteosarcoma chemosensitivity

B15

Background: Despite the increased survival rate of osteosarcoma patients attributed to adjuvant chemotherapy, at least one third of the patients still succumb to their disease. Furthermore, ultra-aggressive combination chemotherapy is associated with considerable acute and long term toxicity. Further improvements in the management of osteosarcoma seemingly depend on diagnostic and prognostic tools that may allow for a more risk adapted and individualized treatment. Non-coding micro RNAs hold great promise as new prognostic biomarkers. In this study, we systematically investigated the micro RNA expression in response to doxorubicin, cisplatin or ifosfamide using osteosarcoma tumor xenografts that are either sensitive or resistant to these compounds.
 Materials and Methods: Fragments of tissue from biopsies or surgically removed tumors from 10 patients with osteosarcoma were implanted s.c. into the flanks of nude mice to established the xenografts. After evaluated the responsiveness to the drugs (doxorubicin, cisplatin and ifosfamide), the xenografts were harvested to quantify micro RNA expression profiles utilizing high throughput Luminex FlexmiRTM Micro RNA expression assay. The clustering and Venn diagram analysis was performed by GeneSpring software to group xenografts based on their sensitivity to each of the three drugs with 2-fold cut off.
 Results: There were 22 micro RNAs associated with doxorubicin sensitivity and 36 and 29 micro RNAs with cisplatin and ifosfamide sensitivity, respectively. Venn diagram analysis showed 3 overlapping micro RNAs (hsa-miR-140, hsa-miR-217, and hsa-miR-431) among the three different drugs. There were 9 overlapping micro RNAs between doxorubicin and cisplatin or cisplatin and ifosfamide. Doxorubicin and ifosfamide shared the other unique 5 micro RNAs. It is interesting to note that hsa-miR-140 was highly over-expressed by an average of nearly 5 fold in the sensitive vs. resistance group for all three drugs. Hsa-miR-140 is reported to be uniquely associated with bone development by targeting histone deacetylases 4, one of the critical targets for anti-cancer therapy due to its critical role in apoptosis.
 Conclusion: We have identified candidate micro RNAs as classifiers to chemosensitivity of osteosarcoma treatment. Some of these micro RNAs may be important in contributing to increased understanding of post-transcriptional and/or translational controls in drug resistance mechanism, and potentially for the development of new therapeutic approaches.