Activated autophagy contributes to the development of lymphatic malformations

Abstract

To investigate the level of autophagy in lymphatic malformations (LMs), and the role of autophagy in the development of LMs, immunohistochemistry was used to examine the expression level of autophagy-related proteins [Beclin-1, Sequestosome 1 p62 (p62), light chain 3 (LC3)], and markers of anti-apoptosis [B cell lymphoma 2 (Bcl-2), phosphorylated extracellular signal-regulated kinase 1/2 (p-Erk1/2)] as well as the maker of proliferation (Ki-67) in samples of LMs and normal skins (SKs). The Pearson's correlation and cluster analyses were performed to determine to relationships between the proteins we tested. The studies using human dermal lymphatic endothelial cells (HDLECs) were carried out for mechanism investigation. Besides, rat models of LMs were established to evaluate the role of autophagy in LMs. The results showed that the autophagy-related proteins we tested, correlated with each other, were significantly increased in LMs compared with SKs samples. In vitro, autophagy, depended on p-Erk1/2, prevented the apoptosis of HDLECs in FBS starvation conditions. Furthermore, the correlation between the autophagy-related proteins, and p-Erk1/2 as well as Bcl-2 in LMs samples was confirmed in LMs samples. In the LM rat model, the inhibition of autophagy suppressed the development of LMs. Our study indicates that autophagy is elevated in LMs, and plays an important role in LMs.