Department of Orthopedics, the Second Affiliated Hospital of Medical College of Zhejiang University, Hangzhou.
Department of Spinal Surgery, Zhuzhou Central Hospital.
Anticancer Drugs. 2022 Mar 1;33(3):257-267. doi: 10.1097/CAD.0000000000001261.
Osteosarcoma (OS) is a highly aggressive bone cancer. Patients with OS frequently develop drug resistance in clinical treatment, and the prognosis has not been improved significantly. There is an urgent need to identify novel markers and therapeutic targets. In this study, we focused on the highly expressed noncoding circular RNA circPDSS1 in OS, and studied its functional roles and downstream targets in OS cells by CCK-8, clone formation assay, transwell assays. Additionally, we performed luciferase reporter assay, RNA pull-down experiment and qRT-PCR to validate the micoRNA targets of circPDSS1. The involvement of circPDSS1 in tumorigenesis was also investigated in mouse xenografts model. The expression of circPDSS1 was significantly upregulated in OS tissues and cell lines. Patients with high circPDSS1 expression were associated with poorer progression-free survival (PFS) and overall survival (OS) as compared to those with low circPDSS1 expression. CircPDSS1 knockdown significantly inhibited the viability, clone formation ability and invasion ability of OS cells, and induced cell apoptosis, which were associated with the upregulation of proapoptotic proteins and the impairment of prosurvival signaling. Molecular mechanism study further demonstrated that circPDSS1 modulates OS cell functions by regulating the expression of miR-502-3p and miR-4436a. Our data suggest that circPDSS1 acts as a molecular sponge of miR-502-3p and miR-4436a regulates the proliferation and invasion of OS cells and promote the malignant progression of OS.
骨肉瘤（OS）是一种高度侵袭性的骨癌。患有 OS 的患者在临床治疗中经常会产生耐药性，且预后并未得到显著改善。因此，迫切需要鉴定新的标志物和治疗靶点。在本研究中，我们重点关注 OS 中高度表达的非编码环状 RNA circPDSS1，并通过 CCK-8、克隆形成实验和 Transwell 实验研究其在 OS 细胞中的功能作用和下游靶点。此外，我们还进行了荧光素酶报告实验、RNA 下拉实验和 qRT-PCR 实验，以验证 circPDSS1 的 microRNA 靶标。我们还在小鼠异种移植模型中研究了 circPDSS1 参与肿瘤发生的情况。结果表明，circPDSS1 在 OS 组织和细胞系中表达显著上调。与低表达 circPDSS1 的患者相比，circPDSS1 高表达的患者无进展生存期（PFS）和总生存期（OS）更差。circPDSS1 敲低显著抑制 OS 细胞的活力、克隆形成能力和侵袭能力，并诱导细胞凋亡，这与促凋亡蛋白的上调和抗生存信号的损害有关。分子机制研究进一步表明，circPDSS1 通过调节 miR-502-3p 和 miR-4436a 的表达来调节 OS 细胞的功能。我们的数据表明，circPDSS1 作为 miR-502-3p 的分子海绵，调节 OS 细胞的增殖和侵袭，并促进 OS 的恶性进展。
