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

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Abstract

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.

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Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, 250014, China

    Qi Xie, Jing Liang & Ju Liu

  2. Department of Blood Transfusion, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China

    Tong-yao Shang

  3. Institutue of Microvascular Medicine, Medical Research Center, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China

    Shuo Feng, Meng-ge Fan & Ju Liu

  4. Graduate School, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250014, China

    Shuo Feng & Meng-ge Fan

  5. Department of Neurosurgery, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China

    Ru-cai Zhan

  6. Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, Jinan, 250014, China

    Liang Zhang

Authors
  1. Qi Xie
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  2. Tong-yao Shang
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  3. Shuo Feng
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  4. Ru-cai Zhan
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  5. Jing Liang
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  6. Meng-ge Fan
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  7. Liang Zhang
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  8. Ju Liu
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Corresponding author

Correspondence to Ju Liu.

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Conflict of Interest Statement

The authors declare that they have no competing interests.

This study was supported by grants from the National Natural Science Foundation of China (No. 81873473 and No. 91939110), Academic Promotion Program of Shandong First Medical University (No. 2019QL014), and Shandong Taishan Scholarship (Ju Liu).

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Xie, Q., Shang, Ty., Feng, S. et al. Hypoxia Inhibits Proliferation of Human Dermal Lymphatic Endothelial Cells via Downregulation of Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 Expression. CURR MED SCI 41, 1192–1197 (2021). https://doi.org/10.1007/s11596-021-2448-5

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  • DOI: https://doi.org/10.1007/s11596-021-2448-5

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