Hypoxia-induced Tie1 Drives Stemness and Cisplatin Resistance in Non-small Cell Lung Carcinoma Cells

Abstract

Background: Drug resistance and metastasis involving hypoxic tumor environment 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: Expression of Tie1 in a pulmonary microvascular endothelial cell line (HPMEC) and in NSCLC cell lines was detected using qRT-PCR and western blot. The effect of Tie1 on cell stemness and migration was examined by sphere-forming assay and transwell assay in NSCLC cells with Tie1 silenced. The regulation of Tie1 by HIF-1α was evaluated by a dual-luciferase reporter assay and chromatinImmune precipitation (ChIP) analysis.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 the 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.

Hypoxia: molecular pathophysiological mechanisms in human diseases

“…In turn, YAP in HCC cells activates the AKT/Mechanistic target of rapamycin (mTOR)/sterol regulatory element-binding protein 1 (SREBP1) pathway which accelerates HCC cell growth by lipogenesis induction [70]. Another neoplastic condition in which hypoxia appears to support tumor stemness and drug resistance is non-small-cell lung carcinoma, in which the hypoxic state contributes to confer cisplatin resistance by overexpressing Tie1 in a HIF-1α-dependent way [67]. This mechanism of crosstalk between hypoxic tumor environment and neoplastic stem cells could also serve as a target for the new treatments.…”

ITCH facilitates proteasomal degradation of TXNIP in hypoxia‐ induced lung cancer cells

“…Under hypoxia, the expression level of hypoxia-inducible factor-1 (HIF-1), which plays a significant role in promoting cancer cell proliferation as well as metastasis, continuously increases. 19,20 In a previous study, the HIF-1α subunit was found to be highly expressed in NSCLC, and its high expression was associated with poor prognosis in NSCLC subjects. 21 Nevertheless, the influence of ITCH and TXNIP on NSCLC requires further investigation.…”

“…Hypoxic conditions in local tissues may be caused by tumor growth, energy metabolism, invasion, or incomplete local blood vessels. Under hypoxia, the expression level of hypoxia‐inducible factor‐1 (HIF‐1), which plays a significant role in promoting cancer cell proliferation as well as metastasis, continuously increases 19,20 . In a previous study, the HIF‐1α subunit was found to be highly expressed in NSCLC, and its high expression was associated with poor prognosis in NSCLC subjects 21 .…”