Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Glypican-5 (GPC5) is a member of heparan sulfate proteoglycans, and its biological importance in initiation and progression of lung cancer remains controversial. In the present study, we revealed that GPC5 transcriptionally enhanced the expression of CTDSP1 (miR-26b host gene) via AhR-ARNT pathway, and such up-regulation of CTDSP1 intracellularly contributed to the inhibited proliferation of lung cancer cells. Moreover, exosomes derived from GPC5-overexpressing human lung cancer cells (GPC5-OE-derived exosomes) had an extracellular repressive effect on human lymphatic endothelial cells (hLECs), leading to decreased tube formation and migration. Comparison between GPC5-WT- and GPC5-OE-derived exosomes showed that miR-26b (embedded within introns of CTDSP1 gene) was significantly up-regulated in GPC5-OE-derived exosomes and critical to the influence on hLECs. On the mechanism, we demonstrated that miR-26b transferred into hLECs directly targeted to PTK2 3’-UTR and led to PTK2 down-regulation, resulting in defects in tube formation and migration of hLECs. By uncovering the regulation network among GPC5, miR-26b, miR-26b host gene (CTDSP1), and target gene (PTK2), our findings demonstrated that GPC5 functioned as a tumor suppressor in human lung cancer.
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Acknowledgements
We thank all patients involved in this study.
Funding
This work was supported by grants from the Natural Science Foundation of China (82072561), the Natural Science Youth Foundation of China (81501971, 31701111, 31700792), Project funded by China Postdoctoral Science Foundation (2018M630603), the Natural Science Youth Foundation of Jiangsu Province (BK20150252, BK20170295), the Human Resource Summit Grant of Jiangsu Province (WSW-142), and the Youth Medical Professionals Foundation of Jiangsu Province (QNRC2016279).
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XY, YZ, JTJ, MJ, and CPW designed this study. XY and YZ performed all experiments; CW and QL collected tissue samples and the clinical data; JW and WWH analyzed and interpreted the data; WQZ, WW, and RC drafted the paper. All authors read and approved the final paper.
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Written consents for publication were obtained from all the patients involved in our study.
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Written informed consent for the biological studies was obtained from each patient involved in the study, and the study was approved by the Ethics Committee of the Third Affiliated Hospital of Soochow University. All animal studies were approved by the Animal Experimental Committee of the Third Affiliated Hospital of Soochow University.
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Yang, X., Chen, Y., Zhou, Y. et al. GPC5 suppresses lung cancer progression and metastasis via intracellular CTDSP1/AhR/ARNT signaling axis and extracellular exosome secretion. Oncogene 40, 4307–4323 (2021). https://doi.org/10.1038/s41388-021-01837-y
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DOI: https://doi.org/10.1038/s41388-021-01837-y
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