State Key Laboratory of Cell Biology. Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 200031, Shanghai, China.
Innovation Center for Cell Signaling Network. Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 200031, Shanghai, China.
Oncogene. 2019 Sep;38(36):6354-6369. doi: 10.1038/s41388-019-0889-0. Epub 2019 Jul 18.
Metastasis is the leading cause of lung cancer-related death. Elucidating the metastasis process can provide new avenues to inhibit this malignant behavior of cancer cells. Here we found that human lung cancers with high Keratin 14 (K14) expression were associated with nodal metastasis and poor survival. Using the Kras/Trp53 lung cancer mouse model, we confirmed that K14-high cancer cells harbored increased metastatic potential. Mechanistic investigation revealed that Gastrokine 1 (Gkn1) expression positively correlated with K14 level, cancer metastasis, and poor patient survival. Importantly, ectopic expression of Gkn1 enhanced the metastatic capability of K14-low cells in vitro and in vivo, whereas knockdown of Gkn1 did the opposite, indicating the importance of Gkn1 in mediating the metastasis of K14-high cells. Further study demonstrated that Gkn1 expression conferred K14-high cells resistance to anoikis, which is critical for cancer metastasis. Collectively, our findings demonstrate that K14-high cells contribute to lung cancer metastasis potentially through inhibition of anoikis via upregulation of Gkn1.
转移是肺癌相关死亡的主要原因。阐明转移过程可以为抑制癌细胞这种恶性行为提供新的途径。在这里，我们发现高表达角蛋白 14（K14）的人类肺癌与淋巴结转移和预后不良有关。使用 Kras/Trp53 肺癌小鼠模型，我们证实 K14 高的癌细胞具有更高的转移潜力。机制研究表明，胃泌素 1（Gkn1）的表达与 K14 水平、癌症转移和患者预后不良呈正相关。重要的是，Gkn1 的异位表达增强了 K14 低细胞在体外和体内的转移能力，而 Gkn1 的敲低则相反，表明 Gkn1 在介导 K14 高细胞的转移中很重要。进一步的研究表明，Gkn1 的表达赋予了 K14 高细胞对失巢凋亡的抗性，这对于癌症转移至关重要。总之，我们的研究结果表明，K14 高的细胞可能通过上调 Gkn1 抑制失巢凋亡来促进肺癌转移。
