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Hypoxia-induced Tie1 drives stemness and cisplatin resistance in non-small cell lung carcinoma cells
Mingyi Shang
Tongren Hospital, Shanghai Jiao Tong University School of Medicine
Corresponding Author
Zhongmin Wang
Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0002-8358-3074
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Cancer Cell International.
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.
Keywords
Tie1, Hypoxia, stemness, HIF-1α, cisplatin resistance
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CURRENT STATUS: Published
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Posted 30 Dec, 2020
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On 18 Jan, 2021
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Editorial decision: Accept
On 19 Dec, 2020
Editor assigned
On 13 Dec, 2020
Submission checks complete
On 13 Dec, 2020
Editor invited
On 13 Dec, 2020
No comments provided
Editorial decision: Minor revision
On 08 Dec, 2020
Review #3 received
Received 06 Dec, 2020
Reviewer #3 agreed
On 30 Nov, 2020
Review #2 received
Received 29 Nov, 2020
Review #1 received
Received 29 Nov, 2020
Reviewer #2 agreed
On 22 Nov, 2020
Reviewer #1 agreed
On 22 Nov, 2020
Reviewers invited
Invitations sent on 21 Nov, 2020
Editor assigned
On 16 Nov, 2020
Submission checks complete
On 16 Nov, 2020
Editor invited
On 16 Nov, 2020
No comments provided
Editorial decision: Major revision
On 08 Sep, 2020
Review #2 received
Received 06 Sep, 2020
Review #3 received
Received 30 Aug, 2020
Review #1 received
Received 28 Aug, 2020
Reviewer #3 agreed
On 16 Aug, 2020
Reviewer #2 agreed
On 15 Aug, 2020
Reviewers invited
Invitations sent on 14 Aug, 2020
Reviewer #1 agreed
On 14 Aug, 2020
Editor assigned
On 06 Aug, 2020
First submitted
On 05 Aug, 2020
Submission checks complete
On 05 Aug, 2020
Editor invited
On 05 Aug, 2020
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This preprint is under consideration at Cancer Cell International. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Primary research
Hypoxia-induced Tie1 drives stemness and cisplatin resistance in non-small cell lung carcinoma cells
Mingyi Shang
Tongren Hospital, Shanghai Jiao Tong University School of Medicine
Corresponding Author
Zhongmin Wang
Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0002-8358-3074
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 3
Posted 30 Dec, 2020
Published
On 18 Jan, 2021
No community comments so far
Editorial decision: Accept
On 19 Dec, 2020
Editor assigned
On 13 Dec, 2020
Submission checks complete
On 13 Dec, 2020
Editor invited
On 13 Dec, 2020
No comments provided
Editorial decision: Minor revision
On 08 Dec, 2020
Review #3 received
Received 06 Dec, 2020
Reviewer #3 agreed
On 30 Nov, 2020
Review #2 received
Received 29 Nov, 2020
Review #1 received
Received 29 Nov, 2020
Reviewer #2 agreed
On 22 Nov, 2020
Reviewer #1 agreed
On 22 Nov, 2020
Reviewers invited
Invitations sent on 21 Nov, 2020
Editor assigned
On 16 Nov, 2020
Submission checks complete
On 16 Nov, 2020
Editor invited
On 16 Nov, 2020
No comments provided
Editorial decision: Major revision
On 08 Sep, 2020
Review #2 received
Received 06 Sep, 2020
Review #3 received
Received 30 Aug, 2020
Review #1 received
Received 28 Aug, 2020
Reviewer #3 agreed
On 16 Aug, 2020
Reviewer #2 agreed
On 15 Aug, 2020
Reviewers invited
Invitations sent on 14 Aug, 2020
Reviewer #1 agreed
On 14 Aug, 2020
Editor assigned
On 06 Aug, 2020
First submitted
On 05 Aug, 2020
Submission checks complete
On 05 Aug, 2020
Editor invited
On 05 Aug, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Cancer Cell International.
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6