Ewing’s sarcoma is an aggressive bone and soft tissue tumor with a high incidence in children and adolescents. Due to its high malignancy and poor prognosis, identification of novel biomarkers for intervention therapies is necessary to improve outcome. The EWS/FLI1 fusion gene is a characteristic of Ewing’s sarcoma in most cases. Sex determining region Y-box 2 (SOX2) is a primary target of EWS/FLI1. It has been identified as an oncogene and linked to apoptotic resistance in several types of cancer. However, its role and regulatory mechanisms in Ewing’s sarcoma are largely unknown. We systematically investigated the role of SOX2 in Ewing’s sarcoma cell lines, human tissue samples and xenograft models. The expression of SOX2 was detected in Ewing’s sarcoma samples by WB and IHC. siRNAs were used to knockdown EWS/FLI1 and SOX2 in A673 and RD-ES cell lines with the efficiencies tested by qRT-PCR and WB. The effect of SOX2 on cell cycle and apoptosis was determined by Flow cytometric and TUNEL assays. Akt overexpression was performed with plasmid. The protein expression of the corresponding factors was examined by WB analysis. Inhibition of SOX2 in vivo was performed by siRNA against SOX2 in xenograft models, and the protein expression of the regulators testified in vitro was examined in xenograft tumors by IHC and WB. The results confirmed that SOX2 was highly expressed in Ewing’s sarcoma and was the target of EWS/FLI1. SOX2 advanced Ewing’s sarcoma cell survival and proliferation by regulating p21, p27 and cyclin-E to facilitate G1/S phase transition and mediating caspase-3, PARP via both extrinsic (Fas and caspase-8) and intrinsic (caspase-9, Bad, Bcl-2 and XIAP) apoptotic pathways to restrain cell apoptotsis. Additionally, SOX2 regulated the cell-cycle progression and apoptosis via activation of the PI3K/Akt signaling pathway. The mechanisms were proved both in vitro and in vivo. The results demonstrate that SOX2 played a central role in promoting Ewing’s sarcoma cell proliferation in vitro and in vivo with the underlying mechanisms expounded. These findings suggest that SOX2 may serve as a potential biomarker for targeted intervention in Ewing’s sarcoma.

Malignant peripheral nerve sheath tumours (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome, neurofibromatosis type 1 (NF1). This study aimed to examine the function of High mobility group protein A2 (HMGA2) in NF1 MPNST progression and the underlying molecular mechanism. Immunohistochemistry (IHC) was used to detect HMGA2 expression in MPNST and neurofibroma patient samples. Cell Cycle Kit-8 (CCK-8) and 5-ethynyl-20-deoxyuridine (EdU) assays, terminal deoxynucleotidyl transferase-mediated nick end labelling, and transmission electron microscopy were performed to reveal HMGA2 functions in NF1 MPNST cells in vitro and in vivo. Chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA sequencing (RNA-Seq) were used to detect HMGA2-modulated genes regulating autophagy and growth in NF1 MPNSTs in vitro and in vivo. NF1 MPNST samples exhibit higher HMGA2 positivity rates (13/16) than sporadic MPNST (16/41) and neurofibroma (0/7) patient samples. High HMGA2 expression is correlated with poor prognosis. Neurofibromin 1 (NF1)-deficient MPNST cells display elevated HMGA2 expression. Functional experiments revealed that HMGA2 knockdown inhibits NF1 MPNST cell growth in vitro and in vivo. In addition to promoting cell cycle arrest and apoptosis, HMGA2 knockdown inhibits autophagy, favouring cell death. RNA-Seq and ChIP-Seq revealed that HMGA2 directly activates the Musashi-2 (MSI2) promoter region, and MSI2 overexpression reverses autophagy and growth in shHMGA2-transfected cells. MSI2 interacts with Beclin1, and Beclin1 blockade inhibits autophagy, thereby inhibiting cell proliferation. HMGA2 knockdown regulates autophagy via MSI2-Beclin1 interactions to inhibit NF1 MPNST growth, revealing potential therapeutic targets for these untreatable tumours.

Malignant peripheral nerve sheath tumours (MPNSTs) are highly aggressive Schwann cell-derived sarcomas, and they are either associated with neurofibromatosis type 1 (NF1) or sporadic. Our previous study found that high mobility group protein A2 (HMGA2) regulates NF1-MPNST growth through Musashi-2 (MSI2); however, whether MSI2 regulates MPNST metastasis and what the mechanism is remain unclear. Here, we demonstrated that the protein caveolin-1 (CAV1) directly interacts with MSI2 in human NF1-MPNST cells. Moreover, we discovered that knockdown of MSI2 induces CAV1 protein expression by inhibiting its ubiquitylation level in NF1-MPNSTs. In addition, CAV1 mediates the suppressive function of MSI2 in epithelial-mesenchymal transition, migration and invasion in vitro and metastasis in vivo. These results help to reveal the potential mechanisms of MSI2 as a target of antimetastatic treatment for human NF1-MPNST.

Malignant bone neoplasms can be represented by osteosarcoma (OS), which accounts for 36% of all sarcomas. To reduce tumor malignancy, extensive efforts have been devoted to find an ideal target from numerous candidates, among which RNA‐binding proteins (RBPs) have shown their unparalleled competitiveness. With the special structure of RNA‐binding domains, RBPs have the potential to establish relationships with RNAs or small molecules and are considered regulators of different sections of RNA processes, including splicing, transport, translation, and degradation of RNAs. RBPs have considerable significant roles in various cancers, and experiments revealed that there was a strong association of RBPs with tumorigenesis and tumor cell progression. Regarding OS, RBPs are a new orientation, but achievements in hand are noteworthy. Higher or lower expression of RBPs was first found in tumor cells compared to normal tissue. By binding to different molecules, RBPs are capable of influencing tumor cell phenotypes through different signaling pathways or other axes, and researches on medical treatment have been largely inspired. Exploring the prognostic and therapeutic values of RBPs in OS is a hotspot where diverse avenues on regulating RBPs have achieved dramatical effects. In this review, we briefly summarize the contribution of RBPs and their binding molecules to OS oncogenicity and generally introduce distinctive RBPs as samples. Moreover, we focus on the attempts to differentiate RBP’s opposite functions in predicting prognosis and collect possible strategies for treatment. Our review provides forwards insight into improving the understanding of OS and suggests RBPs as potential biomarkers for therapies.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.