The mineral dust-induced gene, <em>mdig</em>, regulates angiogenesis and lymphangiogenesis in lung adenocarcinoma by modulating the expression of VEGF-A/C/D via EGFR and HIF-1α signaling

Zhou,Haomin; Geng,Feng; Chen,Yecheng; Du,Juan; Zhang,Xinyu; Liu,Bin; Song,Dandan; Hou,Haijia; Zhao,Hongwen

doi:10.3892/or.2021.8011

The mineral dust-induced gene, mdig, regulates angiogenesis and lymphangiogenesis in lung adenocarcinoma by modulating the expression of VEGF-A/C/D via EGFR and HIF-1α signaling

Authors:
- Haomin Zhou
- Feng Geng
- Yecheng Chen
- Juan Du
- Xinyu Zhang
- Bin Liu
- Dandan Song
- Haijia Hou
- Hongwen Zhao
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Affiliations: Department of Pulmonary Critical Care Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
Published online on: March 12, 2021 https://doi.org/10.3892/or.2021.8011
Article Number: 60

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Abstract

Mineral dust‑induced gene (mdig) is a novel lung cancer‑related oncogene. The aim of this study was to explore the effects of mdig on angiogenesis and lymphangiogenesis by vascular endothelial growth factor (VEGF) in lung adenocarcinoma. mdig‑overexpressing A549, H1299 and 293T cells, mdig‑silenced A549, human umbilical vein endothelial cells (HUVECs) and human lymphatic endothelial cells (HLECs) were cultured under normoxic and hypoxic conditions. Protein expression levels of mdig, epidermal growth factor receptor (EGFR), phospho(p)‑EGFR Tyr1068, hypoxia‑inducible factor‑1α (HIF‑1α), VEGF‑A/C/D and VEGF‑R1/R2/R3 were assessed using western blotting. mRNA expression levels of mdig, EGFR and HIF‑1α were measured using RT‑qPCR. Tube formation and xenograft tumor experiments were performed to examine the mechanism of mdig in angiogenesis and lymphangiogenesis. Protein expression levels of EGFR, HIF‑1α and VEGF‑A/C/D were significantly upregulated in cells cultured under hypoxic conditions compared with those cultured under normoxic conditions, whereas the levels of mdig were decreased. Protein expression levels of EGFR, p‑EGFR and VEGF‑A/R1/R2 were significantly increased in the mdig‑overexpressing cells, whereas the levels of HIF‑1α and VEGF‑C/D/R3 were decreased compared with those in control cells, all of which were reversed in mdig‑silenced cells. Tumor volumes and density of angiogenesis in the mdig‑overexpressing group were significantly increased compared with those in the control group, whereas the density of lymphangiogenesis was decreased. No tumors formed in the mdig‑silenced group after 3 weeks of assessment in vivo. Protein expression levels of EGFR, p‑EGFR, VEGF‑A and angiogenesis density were significantly reduced in the mdig‑overexpressing cells treated with an EGFR inhibitor, whereas the levels of HIF‑1α, VEGF‑C/D and the lymphangiogenesis density were significantly increased in mdig‑overexpressing cells treated with a HIF‑1α agonist. All changes in protein expression were reversed in EGFR agonist and HIF‑1α inhibitor treated mdig‑silenced cells. In conclusion, mdig is an oxygen‑sensitive protein that promotes tumor growth and angiogenesis by activating the EGFR/p‑EGFR/VEGF‑A/VEGF‑R1/R2 pathway and inhibits lymphangiogenesis by blocking the HIF‑1α/VEGF‑C/D/VEGF‑R3 pathway.

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