At present drugs that specifically inhibit

At present, drugs that specifically inhibit YAP activity are not available. In fact, verteporfin, which was originally described as a specific inhibitor of YAP-TEAD interaction, has been recently shown to exert its activity through selective induction of proteotoxicity rather than through YAP inhibition [34]. However, since, as discussed above, AXL blockage is very effective in bypassing resistance, AXL may represent a more promising actionable target for patients' treatment. A clinical trial testing the effect of cabozantinib (a multikinase inhibitor targeting also AXL) is now recruiting selected patients (NCT01639508), and the first clinical trial of the AXL selective inhibitor TP-0903 is expected to start soon (NCT02729298).
Conclusions The following are the supplementary data related to this article.
Competing Interest
Funding This work was funded by the Italian Association for Cancer Research (AIRC); IG grant 15464 to S. G.
Author Contributions
Introduction Osteosarcoma is the most common primary bone malignancy in adolescents, comprising almost 60% of all sarcoma cases [1], [2], [3]. For both low- and high-grade osteosarcomas, metastasis is one of the primary unfavorable factors for prognosis. For example, cause-specific survival for patients with high-grade osteosarcoma was 83.6%, 71.8%, and 65.8% for patients with non-metastatic disease at diagnosis and 48.4%, 30.4%, and 24.0% for patients with metastatic disease at diagnosis after 2, 5, and 10 years, respectively [4], [5]. It is crucial to identify the underlying molecular mechanisms of osteosarcoma invasion and metastasis. According to the CSCs hypothesis, tumor-initiating Necrostatin 1 (TICs) are resistant to chemotherapy and drive tumor growth and metastasis. Osteosarcoma is often heterogeneous, and CSCs may account for drug resistance and tumor relapse [6]. Osteosarcoma stem cells can be identified by the expression of surface markers, including CD133, CD90, etc. and the transcription factors Oct3/4 and Sox2 [7], [8]. High expression of CSCs markers and high proportions of CSCs may contribute to tumor initiation, progression and poor clinical outcome [9], [10]. Long noncoding RNAs (lncRNAs) regulate diverse biological processes in tumor initiation, growth and metastasis through epigenetic, transcriptional and post transcriptional mechanisms [11], [12], [13]. Moreover, lncRNAs have additional functions including control of muscle differentiation, colon cancer stem cell asymmetric division regulation, osteosarcoma stem cell inhibitor, liver cancer stem cell self-renewal repression, or epithelial-to-mesenchymal transition (EMT) suppression in breast cancer [14], [15], [16], [17], [18]. Recently, the lncRNA differentiation antagonizing non-protein coding RNA (DANCR) (NoncodeID:NONHSAG037936.2) was shown to suppress epidermal progenitor differentiation [19]. As reported, DANCR increased the stemness features of hepatocellular carcinoma and was associated with tumor progression and poor prognosis in colorectal cancer [20], [21]. Moreover, DANCR also correlated with the differentiation of mesenchymal tissues, such as chondrogenic differentiation and odontoblast-like differentiation [22], [23]. Based on these findings, we hypothesized that DANCR acts as a regulator of CSCs function during osteosarcoma progression. According to our previous study, the receptor tyrosine kinase AXL is highly expressed in osteosarcoma and is positively related to a poor prognosis [24]. In the present study, we found that over-expression of lncRNA DANCR in tumors was positively correlated with a poor prognosis for osteosarcoma patients and was related to the stemness of cells important for tumor invasion and metastasis. Importantly, we found that DANCR targets AXL mRNA through a novel mechanism by blocking miR-33a-5p. Thus, activation of DANCR has great potential significance as a prognostic biomarker and therapy target for osteosarcoma.
Materials and methods