Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, Korea.
Oncogene. 2020 Jan;39(4):767-785. doi: 10.1038/s41388-019-1023-z. Epub 2019 Sep 23.
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.
早期发现 PLK1 在癌症中高度表达，这促使人们探索其在转移中的功能。然而，PLK1 是否在体内诱导转移以及其在非小细胞肺癌中的潜在机制尚未确定。在这里，我们表明，在 TGF-β 处理的肺细胞中丰富的 T210 磷酸化的活性 PLK1 强烈诱导尾静脉注射模型中的转移。具有完整 polo 框和 ATP 结合结构域的活性 PLK1 通过触发 EMT 重编程，加速细胞迁移和侵袭，而 p-S137-PLK1 的磷酸模拟版本则不能，表明 PLK1 的磷酸化状态可能决定细胞特征。活性 PLK1 驱动的侵袭性上调 TGF-β 信号和由 TNFAIP6 编码的 TSG6。TNFAIP6 的缺失扰乱了活性 PLK1 或 TGF-β 诱导的转移活性。临床相关性表明，PLK1 和 TNFAIP6 是转移性非小细胞肺癌患者生存率低的强有力预测因子。因此，我们认为活性 PLK1 通过上调 TGF-β 信号促进转移，通过形成正反馈环放大其转移特性，并且通过靶向 PLK1 和 TSG6 可以有效阻断 PLK1/TGF-β 驱动的转移，为转移性非小细胞肺癌的预后和治疗靶点提供 PLK1 和 TSG6 作为负标记物。
