Hypoxia-induced Tie1 drives stemness and cisplatin resistance in non-small cell lung carcinoma cells
| Autor: | Ziyin Wang, Zhongmin Wang, Jian Lu, Nannan Yang, Mingyi Shang, Chaojie Li, Qungang Shan, Zhi-Jin Chen, Ning Xia |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Cell HIF-1α medicine.disease_cause lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Genetics medicine lcsh:QH573-671 Stemness Hypoxia Cisplatin resistance 030304 developmental biology Cisplatin 0303 health sciences Reporter gene lcsh:Cytology Chemistry Hypoxia (medical) lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Endothelial stem cell medicine.anatomical_structure Oncology Tie1 030220 oncology & carcinogenesis Cancer research medicine.symptom Stem cell Carcinogenesis Primary Research medicine.drug |
| Zdroj: | Cancer Cell International Cancer Cell International, Vol 21, Iss 1, Pp 1-12 (2021) |
| ISSN: | 1475-2867 |
| Popis: | Background 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). 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. Methods The 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. Results We 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. Conclusions Our 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. |
| Databáze: | OpenAIRE |
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