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Keratin 14-high subpopulation mediates lung cancer metastasis potentially through Gkn1 upregulation

Oncogene volume 38, pages 6354–6369 (2019)Cite this article

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Abstract

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 KrasG12D/Trp53L/L 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.

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Acknowledgements

The authors thank Dr. Tyler Jacks and Dr. Kwok-Kin Wong for kindly providing the KrasG12D/Trp53L/L mice. We are grateful to Dr. Luonan Chen, Ying Tang, and Zaoyuan Fang for providing bioinformatic supports. We thank Dr. Lin He for critical review of the manuscript. This work was supported by the National Basic Research Program of China (Grant 2017YFA0505501), Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDB19020201), the National Natural Science Foundation of China (Grants 81430066, 91731314, 31621003, 81872312, 81871875 and 81802279), and the China Postdoctoral Science Foundation (2016M601667).

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  1. State Key Laboratory of Cell Biology. Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 200031, Shanghai, China

    Shun Yao, Hsin-Yi Huang, Xiangkun Han, Yi Ye, Zhen Qin, Gaoxiang Zhao, Fuming Li, Liang Hu & Hongbin Ji

  2. Innovation Center for Cell Signaling Network. Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 200031, Shanghai, China

    Shun Yao, Hsin-Yi Huang, Xiangkun Han, Yi Ye, Zhen Qin, Gaoxiang Zhao, Fuming Li, Liang Hu & Hongbin Ji

  3. CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 200031, Shanghai, China

    Shun Yao, Hsin-Yi Huang, Xiangkun Han, Yi Ye, Zhen Qin, Gaoxiang Zhao, Fuming Li, Liang Hu & Hongbin Ji

  4. University of Chinese Academy of Sciences, 100049, Beijing, China

    Shun Yao, Zhen Qin & Hongbin Ji

  5. School of Life Science and Technology, Shanghai Tech University, 200120, Shanghai, China

    Yi Ye & Hongbin Ji

  6. The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, 200031, Shanghai, China

    Guohong Hu

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Yao, S., Huang, HY., Han, X. et al. Keratin 14-high subpopulation mediates lung cancer metastasis potentially through Gkn1 upregulation. Oncogene 38, 6354–6369 (2019). https://doi.org/10.1038/s41388-019-0889-0

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