Abstract
Early findings that PLK1 is highly expressed in cancer have driven an exploration of its functions in metastasis. However, whether PLK1 induces metastasis in vivo and its underlying mechanisms in NSCLC have not yet been determined. Here, we show that the expression of active PLK1 phosphorylated at T210, abundant in TGF-β-treated lung cells, potently induced metastasis in a tail-vein injection model. Active PLK1 with intact polo-box and ATP-binding domains accelerated cell motility and invasiveness by triggering EMT reprogramming, whereas a phosphomimetic version of p-S137-PLK1 did not, indicating that the phosphorylation status of PLK1 may determine the cell traits. Active PLK1-driven invasiveness upregulated TGF-β signaling and TSG6 encoded by TNFAIP6. Loss of TNFAIP6 disturbed the metastatic activity induced by active PLK1 or TGF-β. Clinical relevance shows that PLK1 and TNFAIP6 are strong predictors of poor survival rates in metastatic NSCLC patients. Therefore, we suggest that active PLK1 promotes metastasis by upregulating TGF-β signaling, which amplifies its metastatic properties by forming a positive feedback loop and that the PLK1/TGF-β-driven metastasis is effectively blocked by targeting PLK1 and TSG6, providing PLK1 and TSG6 as negative markers for prognostics and therapeutic targets in metastatic NSCLC.
Highlights
40% of the patients newly diagnosed with lung cancer, a leading cause of cancer-related mortality worldwide [1, 2], already have metastases to bone or other sites in the lung, brain, liver, and adrenal glands [3]
Recent studies reported that overexpression of PLK1 induces the epithelial-to-mesenchymal transition (EMT) and promotes cell motility in prostate and gastric cancer [19, 20], it is not yet well understood whether the expression of PLK1 is required to induce metastasis in vivo and in non-small cell lung cancer (NSCLC) cancer patients or which is more important in inducing the EMT for metastasis in NSCLC, the expression of PLK1 or its activation
The active form of PLK1 phosphorylated at T210 is abundant in TGFβ-induced metastatic NSCLC, and the presence of active PLK1 promotes metastasis of NSCLC in vivo
Summary
40% of the patients newly diagnosed with lung cancer, a leading cause of cancer-related mortality worldwide [1, 2], already have metastases to bone or other sites in the lung, brain, liver, and adrenal glands [3]. The 5year survival rates of patients with non-small cell lung cancer (NSCLC), ~85% of all lung cancers, are 10–20% or less, with a median survival of 8 to 10 months [4]. Understanding and regulating the biology of metastasis is needed to improve the cancer therapies and increase the survival rates of NSCLC patients. The activation of TGF-β signaling induces the expression of genes related to mesenchymal regulation, including SNAI1, SNAI2, TWIST, and ZEB1 [8]. Many studies have reported the existence of a partial EMT status or mixture of mesenchymal and epithelial cells used for efficient metastasis and
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