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The keratin 17/YAP/IL6 axis contributes to E-cadherin loss and aggressiveness of diffuse gastric cancer

Oncogene volume 41, pages 770–781 (2022)Cite this article

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Abstract

DGC is a particular aggressive malignancy with poor prognosis. Recent omics studies characterized DGC with CDH1/E-cadherin loss and EMT-signatures. However, the underlying mechanisms for maintaining the aggressive behavior and molecular features of DGC remain unclear. Here, we find that intermediate filaments KRT17 is significantly lower in DGC tissues than that in intestinal gastric cancer tissues and associated with poor prognosis of DGC. We demonstrate that downregulation of KRT17 induces E-cadherin loss, EMT changes, and metastasis behaviors of GC cells. Mechanistically, the loss of intermediate filaments KRT17 induces reorganization of cytoskeleton, further activates YAP signaling, and increases IL6 expression, which contributes to the enhanced metastasis ability of GC cells. Together, these results indicate that KRT17/YAP/IL6 axis contributes to maintaining E-cadherin loss, EMT feature, and metastasis of DGC, providing a new insight into the role of aberrant intermediate filaments in DGC malignancy.

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Fig. 1: Downregulation of KRT17 is associated with worse survival of DGC patients, EMT and metastasis.
Fig. 2: Knockout of KRT17 increases EMT changes, migration and metastasis of GC cells.
Fig. 3: Knockout of KRT17 enhances stem-like properties of GC cells.
Fig. 4: Knockout of KRT17 activates YAP signaling in GC cells.
Fig. 5: IL6 mediates the improvement of EMT, stem-like property and metastatic ability of GC cells induced by KRT17 knockout.
Fig. 6: Down-regulation of KRT17 is associated with malignant progression of GC.

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Data availability

The accession number of RNA-sequencing raw data in this study is No. GSE171879.

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Acknowledgements

We thank Hai Song for providing pcDNA3.1-YAP plasmid. This work was supported by the National Natural Science Foundation of China (31771540, 81972276, 82173040, 91740205, 31620103911), Natural Scientific Foundation of Zhejiang Province, China (LYY19H310011), Fundamental Research Funds for the Central Universities (2021QNA7004).

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  1. These authors contributed equally: Mengjie Li, Xianping Rao.

Authors and Affiliations

  1. Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Mengjie Li, Xianping Rao, Yun Cui, Lu Zhang, Xiang Li, Yijun Zheng, Tianhua Zhou & Wei Zhuo

  2. Cancer Center, Zhejiang University, Hangzhou, China

    Mengjie Li, Xianping Rao, Yun Cui, Lu Zhang, Xiang Li, Yijun Zheng, Lisong Teng, Tianhua Zhou & Wei Zhuo

  3. Institute of Gastroenterology, Zhejiang University, Hangzhou, China

    Mengjie Li, Xianping Rao, Yun Cui, Lu Zhang, Xiang Li, Boya Wang, Tianhua Zhou & Wei Zhuo

  4. Department of Pharmacy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Boya Wang

  5. Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China

    Yijun Zheng & Lisong Teng

  6. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Tianhua Zhou

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Contributions

WZ, TZ, ML and XR designed the experiments and interpreted the results. ML, XR, YC, XL, YZ performed the experiments. ML, LZ, and XR performed the animal experiments. ML, XR, BW, LT analyzed the clinical data. TZ improved the project design. ML, WZ wrote the manuscript, which was further refined by all authors. WZ supervised the overall study.

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Correspondence to Tianhua Zhou or Wei Zhuo.

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Li, M., Rao, X., Cui, Y. et al. The keratin 17/YAP/IL6 axis contributes to E-cadherin loss and aggressiveness of diffuse gastric cancer. Oncogene 41, 770–781 (2022). https://doi.org/10.1038/s41388-021-02119-3

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