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长基因间非编码RNA DIO3OS通过激活转化生长因子-β信号通路促进骨肉瘤转移：骨肉瘤潜在的诊断和免疫治疗靶点

Long intergenic non-coding RNA DIO3OS promotes osteosarcoma metastasis via activation of the TGF-β signaling pathway: a potential diagnostic and immunotherapeutic target for osteosarcoma.

作者信息

Yuan Jinghong, Jia Jingyu, Wu Tianlong, Du Zhi, Chen Qi, Zhang Jian, Wu Zhiwen, Yuan Zhao, Zhao Xiaokun, Liu Jiahao, Guo Jia, Cheng Xigao

机构信息

Department of Orthopaedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 1 Minde Road, Donghu, Nanchang, 330006, Jiangxi, People's Republic of China.

Institute of Orthopaedics of Jiangxi Province, Nanchang, Jiangxi, China.

出版信息

Cancer Cell Int. 2023 Sep 26;23(1):215. doi: 10.1186/s12935-023-03076-5.

DOI:10.1186/s12935-023-03076-5
PMID:37752544
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10521498/
Abstract

BACKGROUND: The aim of this study was to determine the underlying potential mechanisms and function of DIO3OS, a lincRNA in osteosarcoma and clarify that DIO3OS can be used as a potential diagnostic biomarker and immunotherapeutic target. METHODS: The expression matrix data and clinical information were obtained from XENA platform of UCSC and GEO database as the test cohorts. The external validation cohort was collected from our hospital. Bioinformatics analysis was used to annotate the biological function of DIO3OS. Immune infiltration and immune checkpoint analysis were applied to evaluate whether DIO3OS can be used as an immunotherapeutic target. ROC curves and AUC were established to assess the diagnostic value of DIO3OS for differentiating patients from other subtypes sarcoma. The expression analysis was detected by qRT-PCR, western blot, and immunohistochemical. Wound healing assay and Transwell assay were applied to determine the migration and invasion function of DIO3OS in osteosarcoma cell lines. The tail vein injection osteosarcoma cells metastases model was used in this research. RESULTS: High expression of DIO3OS was identified as a risk lincRNA for predicting overall survival of osteosarcoma in test cohort. The outcomes of experiments in vitro and in vivo showed that low expression of DIO3OS limited osteosarcoma tumor metastasis with inhibiting TGF-β signaling pathway. Immune checkpoint genes (CD200 and TNFRSF25) expressions were inhibited in the low DIO3OS expression group. The DIO3OS expression can be applied to reliably distinguish osteosarcoma from lipomatous neoplasms, myomatous neoplasms, nerve sheath tumors, and synovial-like neoplasms. This result was further validated in the validation cohort. CONCLUSIONS: In conclusion, our outcomes indicated that DIO3OS is a potential diagnostic and prognostic biomarker of osteosarcoma, emphasizing its potential as a target of immunotherapy to improve the treatment of osteosarcoma through TGF-β signaling pathway. TRIAL REGISTRATION NUMBER: The present retrospectively study was approved by the Ethics Committee of The Second Affiliated Hospital of Nanchang University [Review (2020) No. (115)].

摘要

背景：本研究旨在确定骨肉瘤中长链非编码RNA DIO3OS的潜在机制和功能，并阐明DIO3OS可作为潜在的诊断生物标志物和免疫治疗靶点。 方法：从UCSC的XENA平台和GEO数据库获取表达矩阵数据和临床信息作为测试队列。外部验证队列来自我院。采用生物信息学分析对DIO3OS的生物学功能进行注释。应用免疫浸润和免疫检查点分析评估DIO3OS是否可作为免疫治疗靶点。绘制ROC曲线并计算AUC，以评估DIO3OS对骨肉瘤患者与其他亚型肉瘤患者的诊断价值。通过qRT-PCR、蛋白质免疫印迹和免疫组织化学检测表达情况。采用伤口愈合实验和Transwell实验检测DIO3OS在骨肉瘤细胞系中的迁移和侵袭功能。本研究采用尾静脉注射骨肉瘤细胞转移模型。 结果：在测试队列中，DIO3OS高表达被确定为预测骨肉瘤总生存期的风险长链非编码RNA。体内外实验结果表明，DIO3OS低表达通过抑制TGF-β信号通路限制骨肉瘤肿瘤转移。低DIO3OS表达组中免疫检查点基因（CD200和TNFRSF25）的表达受到抑制。DIO3OS表达可用于可靠地区分骨肉瘤与脂肪性肿瘤、肌瘤性肿瘤、神经鞘瘤和滑膜样肿瘤。该结果在验证队列中得到进一步验证。 结论：总之，我们的结果表明，DIO3OS是骨肉瘤潜在的诊断和预后生物标志物，强调了其作为免疫治疗靶点的潜力，可通过TGF-β信号通路改善骨肉瘤的治疗。 试验注册号：本回顾性研究已获得南昌大学第二附属医院伦理委员会批准[审查（2020）第（115）号]。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/b4d6b92a7d5f/12935_2023_3076_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/297a467cb087/12935_2023_3076_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/95a3d0a76f61/12935_2023_3076_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/02299b0cba50/12935_2023_3076_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/a9207db22863/12935_2023_3076_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/b4d6b92a7d5f/12935_2023_3076_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/297a467cb087/12935_2023_3076_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/0a2400909673/12935_2023_3076_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/b6701e50c751/12935_2023_3076_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/15bd018d204d/12935_2023_3076_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/95a3d0a76f61/12935_2023_3076_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/02299b0cba50/12935_2023_3076_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/a9207db22863/12935_2023_3076_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b0d5/10521498/b4d6b92a7d5f/12935_2023_3076_Fig8_HTML.jpg

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[3]
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本文引用的文献

[1]
New Horizons in the Treatment of Osteosarcoma.

N Engl J Med. 2021-11-25

[2]
DNA-methylation-induced silencing of DIO3OS drives non-small cell lung cancer progression via activating hnRNPK-MYC-CDC25A axis.

Mol Ther Oncolytics. 2021-10-1

[3]
Dual electrochemical genosensor for early diagnosis of prostate cancer through lncRNAs detection.

Biosens Bioelectron. 2021-11-15

[4]
RETRACTED ARTICLE: Long non-coding RNA DIO3OS binds to microRNA-130b to restore radiosensitivity in esophageal squamous cell carcinoma by upregulating PAX9.

Cancer Gene Ther. 2022-6

[5]
Advancing therapy for osteosarcoma.

Nat Rev Clin Oncol. 2021-10

[6]
The Missing Link Between Cancer-Associated Variants and LncRNAs.

Trends Genet. 2021-5

[7]
Diagnostic, prognostic, and therapeutic significance of long non-coding RNA MALAT1 in cancer.

Biochim Biophys Acta Rev Cancer. 2021-4

[8]
Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma.

Nat Commun. 2020-12-10

[9]
TNK2-AS1 upregulated by YY1 boosts the course of osteosarcoma through targeting miR-4319/WDR1.

Cancer Sci. 2021-2

[10]
LncRNA NR_027471 Functions as a ceRNA for miRNA-8055 Leading to Suppression of Osteosarcoma by Regulating the Expression of TP53INP1.

Front Oncol. 2020-9-29

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