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肿瘤来源的外泌体 lncRNA-SOX2OT 通过靶向破骨细胞中的 miRNA-194-5p/RAC1 信号轴促进非小细胞肺癌骨转移。

Tumour-derived exosomal lncRNA-SOX2OT promotes bone metastasis of non-small cell lung cancer by targeting the miRNA-194-5p/RAC1 signalling axis in osteoclasts.

机构信息

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

出版信息

Cell Death Dis. 2021 Jul 2;12(7):662. doi: 10.1038/s41419-021-03928-w.

DOI:10.1038/s41419-021-03928-w
PMID:34215717
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8253828/
Abstract

Bone is a frequent metastatic site of non-small cell lung cancer (NSCLC), and bone metastasis (BoM) presents significant challenges for patient survival and quality of life. Osteolytic BoM is characterised by aberrant differentiation and malfunction of osteoclasts through modulation of the TGF-β/pTHrP/RANKL signalling pathway, but its upstream regulatory mechanism is unclear. In this study, we found that lncRNA-SOX2OT was highly accumulated in exosomes derived from the peripheral blood of NSCLC patients with BoM and that patients with higher expression of exosomal lncRNA-SOX2OT had significantly shorter overall survival. Additionally, exosomal lncRNA-SOX2OT derived from NSCLC cells promoted cell invasion and migration in vitro, as well as BoM in vivo. Mechanistically, we discovered that NSCLC cell-derived exosomal lncRNA-SOX2OT modulated osteoclast differentiation and stimulated BoM by targeting the miRNA-194-5p/RAC1 signalling axis and TGF-β/pTHrP/RANKL signalling pathway in osteoclasts. In conclusion, exosomal lncRNA-SOX2OT plays a crucial role in promoting BoM and may serve as a promising prognostic biomarker and treatment target in metastatic NSCLC.

摘要

骨是非小细胞肺癌（NSCLC）常见的转移部位，骨转移（BoM）对患者的生存和生活质量提出了重大挑战。溶骨性 BoM 的特征是破骨细胞通过调节 TGF-β/pTHrP/RANKL 信号通路发生异常分化和功能障碍，但其上游调控机制尚不清楚。在这项研究中，我们发现长链非编码 RNA-SOX2OT 在 BoM 的 NSCLC 患者外周血衍生的外泌体中高度积累，并且外泌体 lncRNA-SOX2OT 表达较高的患者总生存期明显缩短。此外，来自 NSCLC 细胞的外泌体 lncRNA-SOX2OT 在体外促进细胞侵袭和迁移，并在体内促进 BoM。从机制上讲，我们发现 NSCLC 细胞衍生的外泌体 lncRNA-SOX2OT 通过靶向 miRNA-194-5p/RAC1 信号轴和破骨细胞中的 TGF-β/pTHrP/RANKL 信号通路调节破骨细胞分化并刺激 BoM。总之，外泌体 lncRNA-SOX2OT 在促进 BoM 中起关键作用，可能成为转移性 NSCLC 有前途的预后生物标志物和治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/be45f9f5190a/41419_2021_3928_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/0d22e6a27d29/41419_2021_3928_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/83d887cc84d6/41419_2021_3928_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/a82672d37c42/41419_2021_3928_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/deeb7142bca6/41419_2021_3928_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/cfae983b6b06/41419_2021_3928_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/6905fdde2792/41419_2021_3928_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/be45f9f5190a/41419_2021_3928_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/0d22e6a27d29/41419_2021_3928_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/83d887cc84d6/41419_2021_3928_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/a82672d37c42/41419_2021_3928_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/deeb7142bca6/41419_2021_3928_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/cfae983b6b06/41419_2021_3928_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/6905fdde2792/41419_2021_3928_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147b/8253828/be45f9f5190a/41419_2021_3928_Fig7_HTML.jpg

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