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KIF14 promotes proliferation, lymphatic metastasis and chemoresistance through G3BP1/YBX1 mediated NF-κB pathway in cholangiocarcinoma

Oncogene volume 42, pages 1392–1404 (2023)Cite this article

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Abstract

Cholangiocarcinoma (CCA), a highly lethal and fetal cancer derived from the hepatobiliary system, is featured by aggressive growth and early lymphatic metastasis. Elucidating the underlying mechanism and identifying the effective therapy are critical for advanced CCA patients. In the study, we detected that KIF14 was upregulated in CCA samples, especially in patients with lymph node metastasis and vascular invasion. CCA patients with higher KIF14 were associated with worse overall survival and recurrence-free survival after surgery. Gain-of and loss-of function studies showed that KIF14 enhanced CCA cells proliferation, migration, invasion and lymphatic metastasis whereas its silencing abolished the effects in vivo and in vitro. Mechanistic investigation showed that KIF14 bound to the G3BP1/YBX1 complex and facilitated their interaction, causing increased activity of the NF-κB promoter and activation of NF-κB pathway. Furthermore, increased KIF14 level enhanced chemotherapy-resistance to gemcitabine-based regimen and induced immunosuppressive microenvironment. In addition, KIF14 was direct target of HNF4A and inversely regulated by HNF4A. Together, these findings suggested that KIF14 could be a potential oncogene and a good indicator in predicting prognosis and chemotherapy guidance for CCA patients.

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Fig. 1: KIF14 was upregulated in CCA and indicated worse survival.
Fig. 2: KIF14 facilitated CCA progression and lymphangiogenesis in vitro.
Fig. 3: KIF14 enhanced CCA growth and lymphatic metastasis in vivo.
Fig. 4: KIF14 bound to the complex of G3BP1/YBX1 and facilitated their interaction.
Fig. 5: KIF14-modulated G3BP1/YBX1 complex increased the transcriptional activity of NF-κB in CCA.
Fig. 6: KIF14 facilitated CCA development in NF-κB pathway dependent manner.
Fig. 7: KIF14 induced chemoresistance and immunosuppressive TME in CCA.

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Data availability

The supporting data of this study can be available by contacting the corresponding author with reasonable request.

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Acknowledgements

The authors would like to thank pathologists in the First Affiliated Hospital of Nanjing Medical University for evaluating HE and IHC slides and Jiangsu Provincial Key Research and Development Program (BE2016789) for supporting our study.

Funding

This work was supported by Jiangsu Provincial Key Research and Development Program (BE2016789).

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  1. These authors contributed equally: Wangjie Jiang, Jifei Wang, Xiao Yang.

Authors and Affiliations

  1. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Wangjie Jiang, Jifei Wang, Xiao Yang, Jijun Shan, Yaodong Zhang, Xiaoli Shi, Yuming Wang, Anlan Chenyan, Jiang Chang, Yirui Wang, Yue Yu, Changxian Li & Xiangcheng Li

  2. Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China

    Yaodong Zhang, Yue Yu, Changxian Li & Xiangcheng Li

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Contributions

Study concept and design: XL and CL; Acquisition of data: JW, YuW, AC, JS, YiW, and JC; Analysis and interpretation of data: WJ, JW, and XY; Drafting of the manuscript: WJ; Critical revision of the manuscript for important intellectual content: XL and CL; Obtained funding: XL and CL; Administrative, technical, or material support: XY and YY; Study supervision: XL and CL.

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Correspondence to Changxian Li or Xiangcheng Li.

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Jiang, W., Wang, J., Yang, X. et al. KIF14 promotes proliferation, lymphatic metastasis and chemoresistance through G3BP1/YBX1 mediated NF-κB pathway in cholangiocarcinoma. Oncogene 42, 1392–1404 (2023). https://doi.org/10.1038/s41388-023-02661-2

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