Abstract
Background
To investigate whether the YAP/TAZ (Yes-associated protein/transcriptional coactivator with PDZ binding motif) pathway contributes to the pathogenesis of lymphatic malformations (LMs).
Methods
YAP, TAZ, CTGF (connective tissue growth factor), and Ki-67 were detected in LMs by immunohistochemistry. The colocalization of YAP and Ki-67 was analyzed by double immunofluorescence. Pearson’s correlation and cluster analyses were performed to analyze the relationships between these proteins. Human dermal lymphatic endothelial cells (HDLECs) were used for mechanistic investigation. Rat models of LMs were established to investigate the role of the YAP pathway in LM development.
Results
Compared with those in normal skin, the expression levels of YAP, TAZ, CTGF, and Ki-67 were significantly upregulated in lymphatic endothelial cells (LECs) of LMs. Interestingly, YAP and CTGF presented much higher expression levels in infected LMs. In experiments in vitro, lipopolysaccharide (LPS) enhanced the expression of YAP in a concentration- and time-dependent manner via the increased phosphorylation of Erk1/2 (extracellular signal-regulated kinase 1/2). Moreover, the proliferation, invasion, and tubule formation of HDLECs increased significantly in accordance with the activation of the YAP signaling pathway. Furthermore, LM rat models validated that LPS facilitated the development of LMs, which was dependent on the activation of YAP.
Conclusions
The data reveal that activation of the YAP signaling pathway in LECs may play a crucial role in the progression of LMs.
Impact
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Compared with that in normal skin, the YAP signaling pathway was activated in LECs of LMs. Inhibiting the YAP signaling pathway attenuated the proliferation, invasion, and tubule formation of HDLECs. Additionally, the activation of the YAP signaling pathway could promote LM development in a rat model.
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Activation of the YAP signaling pathway in LECs may play a crucial role in the progression of LMs.
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The YAP signaling pathway was activated in LMs. Inhibition of the YAP signaling pathway could promote regression of the lesions.
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Acknowledgements
This research was supported by the National Natural Science Foundation of China (81741082 to Y.C., 81800994 to W.Z., 81671008 to J.Z., and 81502708 to K.H.) and the National Health Commission of the People’s Republic of China (2019ZX09302011 to D.M. and Y.C.).
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W.Z. and H.J. performed the immunohistochemical staining, cell experiments, and animal experiments and wrote the manuscript; Y.Z. and K.H. collected clinical data, performed immunohistochemical staining, and analyzed the data; J.Z. collected clinical data and helped design the study; Y.C. designed the study, analyzed the data, revised the manuscript, and is the guarantor of the work; and X.Z. and D.M. performed the cell transfection experiments and revised the paper.
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Zhong, W., Jiang, H., Zou, Y. et al. The YAP signaling pathway promotes the progression of lymphatic malformations through the activation of lymphatic endothelial cells. Pediatr Res 89, 110–117 (2021). https://doi.org/10.1038/s41390-020-0863-0
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DOI: https://doi.org/10.1038/s41390-020-0863-0
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