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27-11-2021 | NSCLC | Original Article

Metformin inhibits human non-small cell lung cancer by regulating AMPK–CEBPB–PDL1 signaling pathway

Authors: Tao Lu, Ming Li, Mengnan Zhao, Yiwei Huang, Guoshu Bi, Jiaqi Liang, Zhencong Chen, Yuansheng Zheng, Junjie Xi, Zongwu Lin, Cheng Zhan, Wei Jiang, Qun Wang, Lijie Tan

Published in: Cancer Immunology, Immunotherapy | Issue 7/2022

Abstract

Metformin has been found to have inhibitory effects on a variety of tumors. However, its effects on non-small cell lung cancer (NSCLC) remain unclear. We demonstrated that metformin could inhibit the proliferation of A549 and H1299 cells. RNA transcriptome sequencing revealed that PDL1 was significantly downregulated in both cell types following treatment with metformin (P < 0.001). Jaspar analysis and chromatin immunoprecipitation showed that CEBPB could directly bind the promoter region of PDL1. Western blotting showed that protein expression of the isoforms CEBPB-LAP*, CEBPB-LAP, and CEBPB-LIP was significantly upregulated and the LIP/LAP ratio was increased. Gene chip analysis showed that PDL1 was significantly upregulated in A549-CEBPB-LAP cells and significantly downregulated in A549-CEBPB-LIP cells (P < 0.05) compared with CEBPB-NC cells. Dual-luciferase reporter gene assay showed that CEBPB-LAP overexpression could promote transcription of PDL1 and CEBPB-LIP overexpression could inhibit the process. Functional assays showed that the changes in CEBPB isoforms affected the function of NSCLC cells. Western blotting showed that metformin could regulate the function of NSCLC cells via AMPK–CEBPB–PDL1 signaling. Animal experiments showed that tumor growth was significantly inhibited by metformin, and atezolizumab and metformin had a synergistic effect on tumor growth. A total of 1247 patients were retrospectively analyzed, including 166 and 1081 patients in metformin and control groups, respectively. The positive rate of PDL1 was lower than that of the control group (HR = 0.338, 95% CI = 0.235–0.487; P < 0.001). In conclusion, metformin inhibited the proliferation of NSCLC cells and played an anti-tumor role in an AMPK–CEBPB–PDL1 signaling-dependent manner.

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Title: Metformin inhibits human non-small cell lung cancer by regulating AMPK–CEBPB–PDL1 signaling pathway
Authors: Tao Lu
Ming Li
Mengnan Zhao
Yiwei Huang
Guoshu Bi
Jiaqi Liang
Zhencong Chen
Yuansheng Zheng
Junjie Xi
Zongwu Lin
Cheng Zhan
Wei Jiang
Qun Wang
Lijie Tan
Publication date: 27-11-2021
Publisher: Springer Berlin Heidelberg
Keywords: NSCLC
Metformin
NSCLC
Published in: Cancer Immunology, Immunotherapy / Issue 7/2022
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-021-03116-x

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