Abstract
A major challenge in osteosarcoma (OS) is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent. We developed a profiling strategy for serum exosomal microRNAs and mRNAs in OS patients with differential chemotherapeutic responses. Twelve miRNAs were up regulated and 18 miRNAs were under regulated significantly in OS patient with poor chemotherapeutic response when compared with those in good chemotherapeutic response (p<0.05). In addition, miR-124, miR133a, miR-199a-3p, and miR-385 were validated and significantly reduced in poorly responded patients with an independent OS cohort. While miR-135b, miR-148a, miR-27a, and miR-9 were significantly over expressed in serum exosomes. Bioinformatic analysis by DIANA-mirPath demonstrated that Proteoglycans in cancer, Hippo signaling pathway, Pathways in cancer, Transcriptional misregulation in cancer, PI3K-Akt signaling pathway, Ras signaling pathway, Ubiquitin mediated proteolysis, Choline metabolism in cancer were the most prominent pathways enriched in quantiles with the miRNA patterns related to poor chemotherapeutic response. Messenger RNAs(mRNAs) includingAnnexin2, Smad2, Methylthioadenosine phosphorylase (MTAP), Cdc42-interacting protein 4 (CIP4), Pigment Epithelium-Derived Factor (PEDF), WW domain-containing oxidoreductase (WWOX), Cell division cycle 5-like (Cdc5L), P27 were differentially expressed in exosomes in OS patients with different chemotherapeutic response. These data demonstrated that exosomal RNA molecules are reliable biomarkers in classifying osteosarcoma with different chemotherapy sensitivity.
Highlights
Osteosarcoma (OS) is one of the most common bone malignancy, which predominately affects young people
Messenger RNAs(mRNAs) includingAnnexin2, Smad2, Methylthioadenosine phosphorylase (MTAP), Cdc42interacting protein 4 (CIP4), Pigment Epithelium-Derived Factor (PEDF), WW domaincontaining oxidoreductase (WWOX), Cell division cycle 5-like (Cdc5L), P27 were differentially expressed in exosomes in OS patients with different chemotherapeutic response
To identify differentially expressed exosomal microRNA pattern in OS patients with good and poor chemotherapeutic responses, we profiled the expression of 746 miRNAs by using TaqMan miRNA arrays in a pilot cohort of 31 healthy controls, 25 OS patients with good response and 28 OS patients with poor response (Supplementary Table 1)
Summary
Osteosarcoma (OS) is one of the most common bone malignancy, which predominately affects young people. The current therapy is aimed to inhibit tumor growth and metastasis by chemotherapy together with clinical surgery, while the 5-year survival rate is still poor [1, 2]. Tumor necrosis, which is evaluated at the time of resection following chemotherapy, www.impactjournals.com/oncotarget is considered as an important prognostic indicator in OS. Chemotherapy inability to cure metastatic disease is possibly responsible for OS progression. Patients with
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