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Translational Therapeutics

G-protein subunit gamma-4 expression has potential for detection, prediction and therapeutic targeting in liver metastasis of gastric cancer

British Journal of Cancer volume 125, pages 220–228 (2021)Cite this article

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Abstract

Background

The liver is the most common site for haematogenous metastasis of gastric cancer, and liver metastasis is fatal.

Methods

We conducted a transcriptomic analysis between metastatic foci in the liver, primary tumour and adjacent tissues from gastric cancer patients with metastasis limited to the liver. We determined mRNA expression levels in tumour tissues of 300 patients with gastric cancer via quantitative RT-PCR. The oncogenic phenotypes of GNG4 were determined with knockdown, knockout and forced expression experiments. We established and compared subcutaneous and liver metastatic mouse xenograft models of gastric cancer to reveal the roles of GNG4 in tumorigenesis in the liver.

Results

GNG4 was upregulated substantially in primary gastric cancer tissues as well as liver metastatic lesions. High levels of GNG4 in primary cancer tissues were associated with short overall survival and the likelihood of liver recurrence. Functional assays revealed that GNG4 promoted cancer cell proliferation, the cell cycle and adhesiveness. Tumour formation by GNG4-knockout cells was moderately reduced in the subcutaneous mouse model and strikingly attenuated in the liver metastasis mouse model.

Conclusions

GNG4 expression may provide better disease monitoring for liver metastasis, and GNG4 may be a novel candidate therapeutic target for liver metastasis.

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Fig. 1: GNG4 is identified as a promising oncogene to develop liver metastasis of gastric cancer.
Fig. 2: High GNG4 expression correlated with the poor survival of patients with gastric cancer, especially in terms of liver metastasis.
Fig. 3: GNG4 promotes malignant phenotypes of gastric cancer cell lines; in vitro and in vivo assays with transient overexpression of GNG4 (oeGNG4) and stable knockout of GNG4 (dGNG4).

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Acknowledgements

We thank Edanz Group (www.edanzediting.com/ac) and Springer Nature Author Services for editing a draft of this paper. This paper was posted on medRxiv prior to submission. https://medrxiv.org/cgi/content/short/2020.08.14.20175034v1; doi: 2020.08.14.20175034v1.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan

    Haruyoshi Tanaka, Mitsuro Kanda, Takashi Miwa, Shinichi Umeda, Koichi Sawaki, Chie Tanaka, Daisuke Kobayashi, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Masahiko Koike & Yasuhiro Kodera

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Contributions

Study concept and design: M.K. and Y.K. Acquisition of the data: M.K., H.T., T.M., S.U., K.S., C.T. and Y.K. Management of data acquisition: M.K., C.T., D.K., M.H., S.Y., G.N., M.K. and Y.K. Analysis of the present data: H.T., M.K. and Y.K. Statistical analysis: H.T. and M.K. Critical interpretation of the present data: H.T., M.K., T.M., S.U., K.S., C.T., D.K., M.H., S.Y., G.N., M.K. and Y.K. Drafting of the paper: H.T., M.K. and Y.K. Critical revision of the paper for important intellectual content: H.T., M.K., T.M., S.U., K.S., C.T., D.K., M.H., S.Y., G.N., M.K. and Y.K. Obtained funding: H.T., M.K. and Y.K. Technical or material support: H.T., M.K., T.M., S.U., K.S., C.T., D.K. and M.K. Study supervision: Y.K.

Corresponding author

Correspondence to Mitsuro Kanda.

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Informed consent for the use of clinical samples and data was obtained from all patients in written manners, consistent with the requirement of the Institutional Review Board at Nagoya University, Japan. All animal experiments were conducted in accordance with the ARRIVE guidelines and were approved by the Animal Research Committee of Nagoya University (no. 30143).

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The authors declare no competing interests.

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This work was supported by a Grant-in-Aid for the Encouragement of Young Scientists (2017, B, 17K16538), the Japanese Society for Gastroenterological Carcinogenesis (2016), Nakayama Cancer Research Institute (2016) and the Yokoyama Foundation for Clinical Pharmacology (2016).

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Tanaka, H., Kanda, M., Miwa, T. et al. G-protein subunit gamma-4 expression has potential for detection, prediction and therapeutic targeting in liver metastasis of gastric cancer. Br J Cancer 125, 220–228 (2021). https://doi.org/10.1038/s41416-021-01366-1

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