IL‑21/IL‑21R inhibit tumor growth and invasion in non‑small cell lung cancer cells via suppressing Wnt/β‑catenin signaling and PD‑L1 expression

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Abstract
Lung cancer is considered to be one of the world's deadliest diseases, with non‑small cell lung cancer (NSCLC) accounting for 85% of all lung cancer cases. The present study aimed to investigate the role and underlying mechanisms of interleukin‑21 (IL‑21), and its receptor IL‑21R, in NSCLC. Lung tissues and blood samples of NSCLC were used to measure IL‑21, IL‑21R and programmed death 1 ligand 1 (PD‑L1) expression using ELISA, western blot and immunohistochemistry analyses. Following treatment with different doses of IL‑21, the proliferation, invasion and migration of human NSCLC cell line A549 was evaluated using a cell counting kit‑8, colony formation, Transwell and scratch wound healing assays, respectively. Additionally, IL‑21R and PD‑L1 expression in A549 cells was detected using western blot analysis and immunofluorescence. IL‑21R silencing was subsequently used to investigate its effects in cell proliferation, invasion and migration. PD‑L1, IL‑1β and tumor necrosis factor α (TNF‑α) expression were measured. Finally, Wnt/β‑catenin signaling expression was evaluated using western blot analysis following treatment with IL‑21. Cells were then treated with lithium chloride (LiCl), which is an agonist of Wnt/β‑catenin signaling, and the levels of PD‑L1, IL‑1β and TNF‑α were detected. The results revealed that IL‑21 and IL‑21R expression in the lung tissues and blood samples of patients with NSCLC were decreased, while PD‑L1 expression was increased, compared with normal tissues or healthy controls. Treatment of A549 cells with IL‑21 upregulated IL‑21R expression, downregulated PD‑L1 and inhibited cell growth and metastasis in a dose‑dependent manner. Following IL‑21R silencing, the effects of IL‑21 treatment were reversed, suggesting that IL‑21 acted on A549 cells through binding to IL‑21R. In addition, the results demonstrated that IL‑21 treatment reduced the expression levels of proteins associated with the Wnt/β‑catenin signaling, whereas activation of Wnt/β‑catenin signaling with the LiCl agonist upregulated PD‑L1, IL‑1β and TNF‑α expression. In conclusion, the IL‑21/IL‑21R axis reduced the growth and invasion of NSCLC cells via inhibiting Wnt/β‑catenin signaling and PD‑L1 expression. The present results may provide a novel molecular target for NSCLC diagnosis and therapy.

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