Hypoxia Inhibits Proliferation of Human Dermal Lymphatic Endothelial Cells via Downregulation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 Expression

Objective Lymphatic endothelial cell (LEC) proliferation is essential for lymphangiogenesis. Hypoxia induces lymphangiogenesis, but it directly inhibits LEC proliferation and the underlying mechanisms have not been fully understood. The aim of this study was to investigate the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in hypoxia-repressed LEC proliferation. Methods Human dermal lymphatic endothelial cells (HDLECs) were cultured under normoxic or hypoxic conditions, and cell proliferation was determined using MTT or CCK-8 assays. CEACAM1 expression was silenced by siRNA transfection. Activation of mitogen-activated protein kinases (MAPKs) was examined by Western blotting and blocked by specific inhibitors. Results Under hypoxia, HDLECs proliferation was suppressed and CEACAM1 expression was downregulated. Silence of CEACAM1 in normoxia inhibited HDLECs proliferation and did not further decrease proliferation in HDLECs in response to hypoxia, suggesting that CEACAM1 may mediate hypoxia-induced inhibition of HDLECs proliferation. In addition, silence of CEACAM1 increased phosphorylation of MAPK molecules: extracellular signal-regulated kinase (ERK), p38 MAPK and Jun N-terminal kinase (JNK) in HDLECs. However, only inhibition of the JNK pathway rescued the reduction of HDLEC proliferation induced by CEACAM1 silence. Conclusion Our results suggested that hypoxia downregulates CEACAM1 expression by activation of the JNK pathway, leading to inhibition of HDLEC proliferation. These findings may help to understand the mechanisms of LEC-specific response to hypoxia and develop novel therapies for pathological lymphangiogenesis.

Automated summary

The study found that hypoxia inhibits the proliferation of HDLECs, and CEACAM1 plays a crucial role in this process. Silencing of CEACAM1 inhibited HDLEC proliferation through activation of the JNK pathway, providing insights into the specific response mechanisms of LECs to hypoxia and potential novel therapies for pathological lymphangiogenesis.