Mineral dust-induced gene (MDIG) is a protooncogene associated with lung cancer that serves a key role in the biological processes of tumorigenesis. The aim of the present study was to determine whether MDIG is involved in cisplatin (DDP) resistance in lung adenocarcinoma, and to investigate the associated molecular mechanism. In the present study, MDIG-knockdown and MDIG-overexpressing A549 cells and DDP-resistant A549/DDP cells were initially constructed, and then the mRNA and protein expression levels of MDIG and ATP-binding cassette (ABC) transporters (ABCB1, ABCC1, ABCG2), and the expression levels of the major associated proteins in the WNT/β-catenin pathway were determined by reverse transcription-quantitative PCR and Western blotting experiments. The results revealed that the mRNA and protein expression levels of MDIG in A549/DDP cells were significantly higher compared with those in A549 cells, and that the protein expression levels of MDIG increased in a dose-dependent manner with increasing DDP concentrations. Overexpression of MDIG in A549 and A549/DDP cells led to an increase in the IC 50 value, whereas silencing of MDIG led to a clear reduction in the IC 50 value. The overexpression of MDIG in the A549 and A549/DDP cells markedly upregulated the mRNA and protein expression levels of ABCB1, ABCC1, ABCG2, WNT family member 5A, WNT family member 3A and active β-catenin, and these were markedly decreased following MDIG silencing. Taken together, these results demonstrated that the DDP resistance of lung adenocarcinoma may be associated with an upregulation of MDIG expression, and that the expression levels of MDIG are positively associated with the degree of DDP resistance. Furthermore, MDIG promoted the expression of ABC transporters in tumor cells by activating the WNT/β-catenin signaling pathway, which may, in turn, lead to DDP resistance in lung adenocarcinoma.

No 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.

Recent studies have indicated that mineral dust-induced gene (MDIG) is an oncogene induced by environmental factors, which has a key role in the development and progression of various tumor types, through epigenetic modifications; however, there are no previous pan-cancer analyses of MDIG. In the present study, a comprehensive pan-cancer analysis of MDIG was performed using public databases. The results demonstrated that MDIG was upregulated in tumor tissue samples compared with normal tissue, that it was present in all cancer cell lines and it was closely associated with the prognosis of patients with different tumor types. Furthermore, MDIG expression was closely associated with the immunological characteristics of the tumor microenvironment (TME), such as the frequency of tumor-infiltrating immune cells, TME-relevant signatures, immunostimulatory genes, immune checkpoint genes, chemokine receptor genes, tumor mutational burden and microsatellite instability. In parallel, high expression of MDIG was associated with improved overall survival of patients and this was verified in a cohort of patients who had received anti-programmed cell death 1 ligand 1 treatment. Furthermore, high expression of MDIG led to multiple drug resistance in The Cancer Genome Atlas-lung adenocarcinoma cohort. In addition, gene set variant analysis and gene set enrichment analysis indicated that MDIG was involved in cell cycle regulation. In vitro experiments suggested that MDIG promoted cell proliferation through the mTOR complex 2/Akt and pyruvate dehydrogenase kinase 1/Akt signaling pathways. In summary, the present study suggests that MDIG may be a prognostic biomarker and therapeutic target for various cancer types.