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Thymosin α1 suppresses migration and invasion of PD-L1 high-expressing non-small-cell lung cancer cells via inhibition of STAT3–MMP2 signaling

Authors Bo C, Wu Q, Zhao H, Li X, Zhou Q

Received 22 June 2018

Accepted for publication 15 September 2018

Published 23 October 2018 Volume 2018:11 Pages 7255—7270

DOI https://doi.org/10.2147/OTT.S177943

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Ms Justinn Cochran

Peer reviewer comments 5

Editor who approved publication: Dr Leo Jen-Liang Su


Cong Bo,1,* Qiang Wu,1,* Hai Zhao,2 Xuebing Li,3 Qinghua Zhou1,3

1Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China; 2Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China; 3Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

*These authors contributed equally to this work

Background: Thymosin α1 (Tα1) is one of the most commonly used immunomodulators for metastatic non-small-cell lung cancer (NSCLC) patients in many countries. Despite the identification of the direct suppression on cancer cell proliferation, little is known about its effect on metastasis and metastasis-related signaling such as matrix metalloproteinases (MMPs) and programmed cell death ligand 1 (PD-L1).
Materials and methods: NSCLC cells with distinguishing PD-L1 expression levels were treated with Tα1. siRNAs were used to knockdown PD-L1. Cell migration and invasion abilities were evaluated by wound-healing and transwell assays. The xenograft model by BALB/c nude mice was constructed to test the inhibitory effect of Tα1 on metastasis in vivo. The expression levels of metastasis-related signaling pathways and key molecules were assessed by Western blot (WB) and quantitative reverse transcriptase PCR (qRT-PCR).
Results: Tα1 significantly suppressed cell migration and invasion in PD-L1 high-expressing H1299, NL9980, and L9981 cells but not in PD-L1 low-expressing A549 or SPC-A-1 cells. This difference was demonstrated by mouse model in vivo as well. Knocking down of PD-L1 significantly impaired the inhibition of cell migration and invasion caused by Tα1 treating in PD-L1 high-expressing cells. Besides, Tα1 inhibited the activation and translocation of STAT3 and the expression of MMP2 in PD-L1 high-expressing NSCLC cells. Moreover, the treatment of STAT3 activator colivelin could partly reverse the Tα1-induced MMP2 suppression and the migration phenotype.
Conclusion: Tα1 significantly suppresses migration and invasion in PD-L1 high-expressing NSCLC cells compared with PD-L1 low-expressing NSCLC cells in vitro and in vivo, through the downregulation of STAT3–MMP2 signaling. These different responses to Tα1, together with the depiction of Tα1-induced signaling changes, suggest a potential benefit of Tα1 for PD-L1-positive NSCLC patients, enlightening the combination of Tα1 with target therapy or immune checkpoint inhibitors.

Keywords: matrix metalloproteinase 2, non-small-cell lung cancer, programmed cell death ligand 1, STAT3, thymosin α1
 

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