Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China.
Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China.
Cell Death Dis. 2018 Jul 10;9(7):772. doi: 10.1038/s41419-018-0813-5.
Osteosarcoma (OS) is the most common pediatric malignant bone tumor, and occurrence of pulmonary metastasis generally causes a rapid and fatal outcome. Here we aimed to provide clues for exploring the mechanism of tumorigenesis and pulmonary metastasis for OS by comprehensive analysis of microRNA (miRNA), long non-coding RNA (lncRNA), and mRNA expression in primary OS and OS pulmonary metastasis. In this study, deep sequencing with samples from primary OS (n = 3), pulmonary metastatic OS (n = 3), and normal controls (n = 3) was conducted and differentially expressed miRNAs (DEmiRNAs), lncRNAs (DElncRNAs), and mRNAs (DEmRNAs) between primary OS and normal controls as well as pulmonary metastatic and primary OS were identified. A total of 65 DEmiRNAs, 233 DElncRNAs, and 1405 DEmRNAs were obtained between primary OS and normal controls; 48 DEmiRNAs, 50 DElncRNAs, and 307 DEmRNAs were obtained between pulmonary metastatic and primary OS. Then, the target DEmRNAs and DElncRNAs regulated by the same DEmiRNAs were searched and the OS tumorigenesis-related and OS pulmonary metastasis-related competing endogenous RNA (ceRNA) networks were constructed, respectively. Based on these ceRNA networks and Venn diagram analysis, we obtained 3 DEmiRNAs, 15 DElncRNAs, and 100 DEmRNAs, and eight target pairs including miR-223-5p/(CLSTN2, AC009951.1, LINC01705, AC090673.1), miR-378b/(ALX4, IGSF3, SULF1), and miR-323b-3p/TGFBR3 were involved in both tumorigenesis and pulmonary metastasis of OS. The TGF-β superfamily co-receptor TGFBR3, which is regulated by miR-323b-3p, acts as a tumor suppressor in OS tumorigenesis and acts as a tumor promoter in pulmonary metastatic OS via activation of the epithelial-mesenchymal transition (EMT) program.In conclusion, the OS transcriptome (miRNA, lncRNA, and mRNA) is dynamically regulated. These analyses might provide new clues to uncover the molecular mechanisms and signaling networks that contribute to OS progression, toward patient-tailored and novel-targeted treatments.
骨肉瘤（OS）是最常见的儿童恶性骨肿瘤，发生肺转移通常导致快速和致命的结果。在这里，我们旨在通过综合分析原发性 OS 和 OS 肺转移中的 miRNA（miRNA）、长非编码 RNA（lncRNA）和 mRNA 的表达，为探索 OS 的肿瘤发生和肺转移机制提供线索。在这项研究中，对来自原发性 OS（n=3）、肺转移 OS（n=3）和正常对照（n=3）的样本进行了深度测序，并鉴定了原发性 OS 与正常对照之间以及肺转移和原发性 OS 之间差异表达的 miRNA（DEmiRNAs）、lncRNA（DElncRNAs）和 mRNA（DEmRNAs）。在原发性 OS 与正常对照之间获得了 65 个 DEmiRNAs、233 个 DElncRNAs 和 1405 个 DEmRNAs；在肺转移和原发性 OS 之间获得了 48 个 DEmiRNAs、50 个 DElncRNAs 和 307 个 DEmRNAs。然后，搜索了受同一 DEmiRNAs 调控的靶 DEmRNAs 和 DElncRNAs，并分别构建了 OS 肿瘤发生相关和 OS 肺转移相关的竞争性内源 RNA（ceRNA）网络。基于这些 ceRNA 网络和 Venn 图分析，我们获得了 3 个 DEmiRNAs、15 个 DElncRNAs 和 100 个 DEmRNAs，以及包括 miR-223-5p/（CLSTN2、AC009951.1、LINC01705、AC090673.1）、miR-378b/（ALX4、IGSF3、SULF1）和 miR-323b-3p/TGFBR3 在内的 8 个靶对，它们均参与了 OS 的肿瘤发生和肺转移。受 miR-323b-3p 调控的 TGF-β 超家族共受体 TGFBR3 在 OS 肿瘤发生中作为肿瘤抑制因子发挥作用，而在肺转移 OS 中通过激活上皮-间充质转化（EMT）程序作为肿瘤促进因子发挥作用。总之，OS 转录组（miRNA、lncRNA 和 mRNA）受到动态调控。这些分析可能为揭示促进 OS 进展的分子机制和信号网络提供新线索，以实现针对患者的个体化治疗和新的靶向治疗。
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