Abstract
PD-L1 is overexpressed in tumor cells and contributes to cancer immunoevasion. However, the role of the tumor cell-intrinsic PD-L1 in cancers remains unknown. Here we show that PD-L1 regulates lung cancer growth and progression by targeting the WIP and β-catenin signaling. Overexpression of PD-L1 promotes tumor cell growth, migration and invasion in lung cancer cells, whereas PD-L1 knockdown has the opposite effects. We have also identified WIP as a new downstream target of PD-L1 in lung cancer. PD-L1 positively modulates the expression of WIP. Knockdown of WIP also inhibits cell viability and colony formation, whereas PD-L1 overexpression can reverse this inhibition effects. In addition, PD-L1 can upregulate β-catenin by inhibiting its degradation through PI3K/Akt signaling pathway. Moreover, we show that in lung cancer cells β-catenin can bind to the WIP promoter and activate its transcription, which can be promoted by PD-L1 overexpression. The in vivo experiments in a human lung cancer mouse model have also confirmed the PD-L1-mediated promotion of tumor growth and progression through activating the WIP and β-catenin pathways. Furthermore, we demonstrate that PD-L1 expression is positively correlated with WIP in tumor tissues of human adenocarcinoma patients and the high expression of PD-L1 and WIP predicts poor prognosis. Collectively, our results provide new insights into understanding the pro-tumorigenic role of PD-L1 and its regulatory mechanism on WIP in lung cancer, and suggest that the PD-L1/Akt/β-catenin/WIP signaling axis may be a potential therapeutic target for lung cancers.
Highlights
Lung cancer is one of the most common and aggressive cancers with the highest incidence and lethality[1]
We investigated the role of PD-L1 in the regulation of cell proliferation, migration, invasion, and tumor growth in lung cancer cells and mouse model
PD-L1 regulates lung cancer cell growth in vitro and in vivo PD-L1 plays an important role in tumor immune evasion
Summary
Lung cancer is one of the most common and aggressive cancers with the highest incidence and lethality[1]. The treatment strategies for lung cancer include chemotherapy, radiotherapy, molecular targeting therapy, and immunotherapy. More and more studies have shown that tumor-induced immune suppression is responsible for tumor progression[5,6,7], and for inhibition of anti-tumor treatment[8]. One of the major immune evasion molecules is programmed death-ligand 1 (PD-L1, CD274), which can inhibit the activation of T cells[9]. Previous studies have shown that PD-L1 plays an important role in pregnancy maintenance. PD-L1 is associated with tumor growth and progression. It is highly expressed in various cancers, such as melanoma, non-small cell lung cancer (NSCLC), Official journal of the Cell Death Differentiation Association
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