Abstract
BackgroundDrug resistance and metastasis involving hypoxic tumor environments and persistent stem cell populations are detrimental to the survival of patients with non-small cell lung carcinoma (NSCLC). Tie1 is upregulated in hypoxia and is believed to counteract the effectiveness of platinum agents by promoting the stemness properties in cells. We have investigated the association of Tie1 with HIF-1α and cisplatin resistance in NSCLC cell lines.MethodsThe expression of Tie1 in a pulmonary microvascular endothelial cell line (HPMEC) and NSCLC cell lines was detected using qRT-PCR and western blotting. The effect of Tie1 on cell stemness and migration was examined by sphere-forming and transwell assays in NSCLC cells with Tie1 silenced. The regulation of Tie1 by HIF-1α was evaluated by a dual-luciferase reporter assay and chromatin immunoprecipitation.ResultsWe found that hypoxia could induce stemness and cisplatin resistance in vitro. Tie1 was expressed at low levels in NSCLC cells when compared with human pulmonary microvascular endothelial cells, however, its expression was increased by hypoxia. Additionally, Tie1 knockdown could reduce stemness properties and increase sensitivity to cisplatin in vitro and in a xenograft mouse model. The promoter of Tie1 contains two predicted hypoxia-response elements (HREs). We mutated both HRE sites and conducted chromatin immune-precipitation and promoter luciferase reporter assays and were able to conclude that the induction of Tie1 by hypoxia was HIF-1α-dependent.ConclusionsOur findings indicated that Tie1 is upregulated in a hypoxic environment by HIF-1α and contributes to tumorigenesis and cisplatin resistance through the promotion of stemness in NSCLC cells.
Highlights
Drug resistance and metastasis involving hypoxic tumor environments and persistent stem cell populations are detrimental to the survival of patients with non-small cell lung carcinoma (NSCLC)
Increased Tie1 expression in hypoxic lung cancer cells contributes to a reduction in cisplatin sensitivity To assess the activity of Tie1, we first compared its expression in a pulmonary microvascular endothelial cell line (HPMEC) and NSCLC cell lines (A549, NCI-H460, NCI-H520, and NCI-H1975)
These results indicate that under normoxic conditions, Tie1 expression is lower in NSCLC cells than in normal dividing cells but under hypoxic conditions, such as that found in tumor microenvironments, the expression of Tie1 significantly increases
Summary
Drug resistance and metastasis involving hypoxic tumor environments and persistent stem cell populations are detrimental to the survival of patients with non-small cell lung carcinoma (NSCLC). Tie is upregulated in hypoxia and is believed to counteract the effectiveness of platinum agents by promoting the stemness properties in cells. We have investigated the association of Tie with HIF-1α and cisplatin resistance in NSCLC cell lines. Drug resistance can contribute to high mortality [6], with cancer stem cells (CSCs) emerging as a possible instigator in tumor progression, metastasis, and drug resistance [7]. The drugs used most often in first-line chemotherapy for NSCLC are platinum agents such as cisplatin or carboplatin with paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, or pemetrexed [8]. Acquired resistance or intolerance to these drugs has led to a need for therapies that are more targeted [9]
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