4.7 Article

Hypoxia-induced Tie1 drives stemness and cisplatin resistance in non-small cell lung carcinoma cells

期刊

CANCER CELL INTERNATIONAL
卷 21, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s12935-020-01729-3

关键词

Tie1; Hypoxia; Stemness; HIF-1 alpha; Cisplatin resistance

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资金

  1. Key Program of Shanghai Science and Technology Association [16411952600]
  2. Shanghai Nature Science Foundation [19ZR1432600]
  3. Shanghai Key Specialty Construction Project [ZK2019A02]
  4. Shanghai Municipal Key Clinical Specialty [shslczdzk06002, shslczdzk07002]
  5. Shanghai Municipal Health Bureau [201640125]

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Our study revealed that Tie1 is upregulated in a hypoxic environment in non-small cell lung carcinoma (NSCLC) cells, promoting stemness and resistance to cisplatin. Silencing Tie1 reduced stemness properties and increased sensitivity to cisplatin, suggesting its role in tumorigenesis and drug resistance in NSCLC. Additionally, Tie1 expression was induced by hypoxia in an HIF-1 alpha-dependent manner, further supporting its involvement in promoting stemness and drug resistance in NSCLC.
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-1 alpha 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-1 alpha 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-1 alpha-dependent. Conclusions: Our findings indicated that Tie1 is upregulated in a hypoxic environment by HIF-1 alpha and contributes to tumorigenesis and cisplatin resistance through the promotion of stemness in NSCLC cells.

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