Abstract：
Lung cancer is the most diagnosed malignant cancer and the leading cause of cancer-related deaths worldwide, with advanced stage and metastasis being a major issue. The mechanism leading to metastasis is not yet understood. Here, we found that KRT16 is upregulated in metastatic lung cancer tissues and correlated with poor overall survival. Knockdown of KRT16 inhibits metastasis of lung cancer both in vitro and in vivo. Mechanistically, KRT16 interacts with vimentin, and depletion of KRT16 leads to downregulation of vimentin. KRT16 acquired its oncogenic ability by stabilizing vimentin, and vimentin is required for KRT16-driven metastasis. FBXO21 mediates the polyubiquitination and degradation of KRT16, and vimentin inhibits KRT16 ubiquitination and degradation by impairing its interaction with FBXO21. Significantly, IL-15 inhibits metastasis of lung cancer in a mouse model through upregulation of FBXO21, and the level of IL-15 in circulating serum was significantly higher in nonmetastatic lung cancer patients than in metastatic patients. Our findings indicate that targeting the FBXO21/KRT16/vimentin axis may benefit lung cancer patients with metastasis.
摘要：
肺癌是全球诊断最多的恶性肿瘤，也是癌症相关死亡的主要原因。晚期和转移是一个主要问题。导致转移的机制尚不清楚。这里,我们发现,KRT16在转移性肺癌组织中上调,并与低总生存率相关.KRT16的敲低在体外和体内均抑制肺癌的转移。机械上,KRT16与波形蛋白相互作用，KRT16的耗尽导致波形蛋白的下调。KRT16通过稳定波形蛋白获得其致癌能力，波形蛋白是KRT16驱动的转移所必需的。FBXO21介导KRT16的多泛素化和降解，波形蛋白通过削弱其与FBXO21的相互作用来抑制KRT16的泛素化和降解。重要的是,IL-15通过上调FBXO21抑制小鼠模型中肺癌的转移，非转移性肺癌患者循环血清中IL-15的水平明显高于转移性患者。我们的研究结果表明，靶向FBXO21/KRT16/波形蛋白轴可能有利于肺癌转移患者。
