Abstract
The prerequisite function of vimentin for the epithelial–mesenchymal transition (EMT) is not clearly elucidated yet. Here, we show that vimentin phosphorylated by PLK1, triggers TGF-β-signaling, which consequently leads to metastasis and PD-L1 expression for immune suppression in lung adenocarcinoma. The clinical correlation between expression of both vimentin and PLK1, and overall survival rates of patients was significant in lung adenocarcinoma but not in squamous cell carcinoma. The phosphorylation of vimentin was accompanied by the activation of PLK1 during TGF-β-induced EMT in lung adenocarcinoma. Among the several phosphorylation sites determined by phospho-proteomic analysis and the site-specific mutagenesis, the phosphorylation at S339 displayed the most effective metastasis and tumourigenesis with the highest expression of PD-L1, compared with that of wild-type and other versions in both 3D cell culture and tail-vein injection metastasis models. Phosphomimetic vimentin at S339 interacted with p-Smad2 for its nuclear localization, leading to the expression of PD-L1. Clinical relevance revealed the inverse correlation between the survival rates of patients and the expressions of VIM, PLK1, and CD274 in primary and metastatic lung adenocarcinoma. Thus, PLK1-mediated phosphorylation of vimentin activates TGF-β signaling pathway, leading to the metastasis and immune escape through the expression of PD-L1, functioning as a shuttling protein in lung adenocarcinoma.
Highlights
Lung adenocarcinoma (LUAD) is one of the most aggressive and lethal cancers, which accounts for ≈40% of all lung cancers, with average overall survival (OS) of less than 5 years, as it is often diagnosed at advanced stages [1]
Since active PLK1 and vimentin were high in Transforming growth factor (TGF)-β-treated LUAD (Fig. 1e–h), we investigated whether vimentin is regulated by PLK1 in TGF-βinduced metastatic LUAD
Correlation between expression of vimentin, a canonical marker of epithelial–mesenchymal transition (EMT), and malignancy has been broadly studied; [14,15,16,17, 21] how vimentin regulates tumor metastasis and survival remains under investigation
Summary
Lung adenocarcinoma (LUAD) is one of the most aggressive and lethal cancers, which accounts for ≈40% of all lung cancers, with average overall survival (OS) of less than 5 years, as it is often diagnosed at advanced stages [1]. According to recent data (https://seer.cancer.gov/statfacts/), metastasis rather than the primary tumors is the major cause of death in cancer patients [2, 3]. In the early stages of metastasis, epithelial cells undergo changes in morphogenesis Edited by X.
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