Department of Pulmonary Critical Care Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
Oncol Rep. 2021 May;45(5). doi: 10.3892/or.2021.8011. Epub 2021 Mar 24.
Mineral dust‑induced gene () 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 . 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.
矿物尘埃诱导基因()是一种新的肺癌相关癌基因。本研究旨在探讨在肺腺癌中通过血管内皮生长因子(VEGF)介导的mdig 对血管生成和淋巴管生成的影响。在常氧和低氧条件下培养mdig 过表达的 A549、H1299 和 293T 细胞、mdig 沉默的 A549、人脐静脉内皮细胞(HUVECs)和人淋巴管内皮细胞(HLECs)。采用 Western blot 检测 mdig、表皮生长因子受体(EGFR)、磷酸化(p)-EGFR Tyr1068、缺氧诱导因子-1α(HIF-1α)、VEGF-A/C/D 和 VEGF-R1/R2/R3 的蛋白表达水平。采用 RT-qPCR 检测 mdig、EGFR 和 HIF-1α 的 mRNA 表达水平。进行管形成和异种移植肿瘤实验，以研究 mdig 在血管生成和淋巴管生成中的作用机制。与常氧条件下培养的细胞相比，低氧条件下培养的细胞中 mdig 的蛋白表达水平显著下调，而 EGFR、HIF-1α 和 VEGF-A/C/D 的蛋白表达水平显著上调。与对照组相比，mdig 过表达细胞中 EGFR、p-EGFR 和 VEGF-A/R1/R2 的蛋白表达水平显著增加，而 HIF-1α 和 VEGF-C/D/R3 的蛋白表达水平显著降低，这些变化在 mdig 沉默细胞中均被逆转。mdig 过表达组的肿瘤体积和血管生成密度明显高于对照组，而淋巴管生成密度则降低。在 3 周的评估后，mdig 沉默组没有形成肿瘤。在 mdig 过表达细胞中用 EGFR 抑制剂处理后，EGFR、p-EGFR、VEGF-A 和血管生成密度的蛋白表达水平显著降低，而在用 HIF-1α 激动剂处理的 mdig 过表达细胞中，HIF-1α、VEGF-C/D 和淋巴管生成密度的蛋白表达水平显著增加。在 EGFR 激动剂和 HIF-1α 抑制剂处理的 mdig 沉默细胞中，所有蛋白表达的变化均被逆转。总之，mdig 是一种氧敏感蛋白，通过激活 EGFR/p-EGFR/VEGF-A/VEGF-R1/R2 通路促进肿瘤生长和血管生成，通过阻断 HIF-1α/VEGF-C/D/VEGF-R3 通路抑制淋巴管生成。
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