Department of Bone and Soft Tissue, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Bone and Soft Tissue, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
Cancer Med. 2019 Jul;8(8):3981-3991. doi: 10.1002/cam4.2320. Epub 2019 May 31.
Osteosarcoma is the most common type of primary malignant tumor of skeletal with poor prognosis in children and adolescents. Accumulating evidence indicates that CBX2 is overexpressed in multiple human neoplasm and play a critical role in tumorigenesis and progression. However, its functional role and upstream regulation mechanism in osteosarcoma remain unknown. In the present study, tissue microarray (TMA) analysis was performed to determine the association between CBX2 expression and clinical prognosis of osteosarcoma patients by immunohistochemistry. We also investigated the functional role of CBX2 using small interfering RNA (siRNA) in vitro and in vivo. Additionally, we confirmed the direct binding between CBX2 and let-7a via qPCR, western blot and luciferase reporter assay. We found that CBX2 is dramatically upregulated in osteosarcoma tissues and high CBX2 expression was correlated with metastasis, recurrence, and chemotherapy response, as well as unfavorable prognosis in patients with osteosarcoma. Similar results were observed in a sarcoma cohort from The Cancer Genome Atlas (TCGA) dataset. Further experiments revealed that CBX2 knockdown significantly impeded osteosarcoma cell proliferation and invasion ability in vitro, and suppressed the tumor growth in tumor xenografts model. Mechanistically, we confirmed that CBX2 is a functional target of miRNA let-7a. Overexpression of let-7a inhibits osteosarcoma cell proliferation, which was reversed by CBX2 overexpression. Taken together, our study demonstrates that let-7a/CBX2 plays a crucial role in osteosarcoma progression. CBX2 could serve as a promising prognostic biomarker and potential therapeutic target for osteosarcoma patients.
成骨肉瘤是儿童和青少年中最常见的原发性恶性骨肿瘤，预后较差。越来越多的证据表明，CBX2 在多种人类肿瘤中过度表达，在肿瘤发生和进展中发挥着关键作用。然而，其在成骨肉瘤中的功能作用和上游调控机制尚不清楚。本研究通过免疫组织化学法，利用组织微阵列（TMA）分析来确定 CBX2 表达与成骨肉瘤患者临床预后之间的关系。我们还通过体外和体内实验研究了 CBX2 的功能作用。此外，我们通过 qPCR、western blot 和荧光素酶报告实验证实了 CBX2 与 let-7a 之间的直接结合。结果发现，CBX2 在成骨肉瘤组织中明显上调，高 CBX2 表达与转移、复发、化疗反应以及成骨肉瘤患者的不良预后相关。在 TCGA 数据集的肉瘤队列中也观察到了类似的结果。进一步的实验表明，CBX2 敲低显著抑制了成骨肉瘤细胞在体外的增殖和侵袭能力，并抑制了肿瘤异种移植模型中的肿瘤生长。机制上，我们证实 CBX2 是 miRNA let-7a 的功能靶标。let-7a 的过表达抑制成骨肉瘤细胞的增殖，而 CBX2 的过表达则逆转了这一作用。总之，本研究表明 let-7a/CBX2 在成骨肉瘤进展中起着重要作用。CBX2 可以作为成骨肉瘤患者有前途的预后标志物和潜在治疗靶点。
