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Cellular and Molecular Biology

Hepatic metastasis of gastric cancer is associated with enhanced expression of ethanolamine kinase 2 via the p53–Bcl-2 intrinsic apoptosis pathway

Abstract

Background

Gastric cancer (GC) with hepatic metastasis has a poor prognosis. Understanding the molecular mechanisms involved in hepatic metastasis may contribute to the development of sensitive diagnostic biomarkers and novel therapeutic strategies.

Methods

We performed transcriptome analysis of surgically resected specimens from patients with advanced GC. One of the genes identified as specifically associated with hepatic metastasis was selected for detailed analysis. GC cell lines with knockout of the candidate gene were evaluated in vitro and in vivo. Expression of the candidate gene was analysed in GC tissues from 300 patients.

Results

Ethanolamine kinase 2 (ETNK2) was differentially upregulated in GC patients with hepatic metastasis. ETNK2 expression was elevated in GC cell lines derived from haematogenous metastases. ETNK2 knockout significantly suppressed proliferation, invasion, and migration; increased apoptosis; reduced Bcl-2 protein expression; and increased phosphorylated p53 expression. In mouse xenograft models, ETNK2 knockout virtually abolished hepatic metastasis. Stratification of GC patients based on ETNK2 mRNA level revealed significant associations between high ETNK2 tumour expression and both hepatic recurrence and worse prognosis.

Conclusions

Upregulation of ETNK2 in GC enhances hepatic metastasis, possibly via dysregulation of p53Bcl-2-associated apoptosis. ETNK2 expression may serve as a biomarker for predicting hepatic recurrence and a therapeutic target.

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Fig. 1: ETNK2 is upregulated in human GC cell lines and promotes malignant behaviours.
Fig. 2: ETNK2 knockdown and overexpression influence the proliferation and migration of GC cells.
Fig. 3: ETNK2 knockout promotes cell cycle arrest and apoptosis of GC cells.
Fig. 4: ETNK2 knockout reduces the growth and hepatic metastasis of GC cells in a mouse xenograft model.
Fig. 5: ETNK2 mRNA expression in clinical GC tissues is significantly associated with hepatic recurrence and prognosis.

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Acknowledgements

We thank Anne M. O’Rourke, Ph.D., from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

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Contributions

M. Kanda, Y.K., and T.M. made substantial contributions to conception and design. T.M., M. Koike, S.U., K.S., and H.T. made substantial contributions to acquisition of data. D.S., C.T., N.H., M.H., S.Y., and G.N. made substantial contributions to statistical analysis and interpretation of data. T.M. wrote the draft of manuscript. All authors agreed to be accountable for all aspects of the work and approved the final version of the manuscript.

Corresponding author

Correspondence to Mitsuro Kanda.

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This study conforms with the ethical guidelines of the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects (2013). The Institutional Review Board of Nagoya University approved this study (approval no. 2014-0043). Written informed consent was obtained from all patients. The Animal Research Committee of Nagoya University approved the experiments using animals (approval no. 28210).

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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The authors declare no competing interests.

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This work was supported by grants from the Ichihara International scholarship foundation 2017 and the Okinaka Memorial Institute for Medical Research 2016.

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Miwa, T., Kanda, M., Shimizu, D. et al. Hepatic metastasis of gastric cancer is associated with enhanced expression of ethanolamine kinase 2 via the p53–Bcl-2 intrinsic apoptosis pathway. Br J Cancer 124, 1449–1460 (2021). https://doi.org/10.1038/s41416-021-01271-7

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