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Cellular and Molecular Biology

Mitochondrial matrix protein C14orf159 attenuates colorectal cancer metastasis by suppressing Wnt/β-catenin signalling

Abstract

Background

The mechanisms underlying metastasis of colorectal cancer (CRC) remain unclear. C14orf159 is a mitochondrial matrix protein converting d-glutamate to 5-oxo-d-proline. Other metabolic functions of C14orf159, especially on mitochondrial metabolism, and its contribution to CRC metastasis, are not elucidated.

Methods

Metabolome analysis by gas chromatography-mass spectrometry, RNA-sequencing analysis, flow cytometry, migration and invasion assay, sphere-formation assay using C14orf159-knockout and -stable expressing cells, immunohistochemistry of C14orf159 in human CRC specimens, and xenograft experiments using Balb/c nude mice were conducted.

Results

C14orf159 maintained the mitochondrial membrane potential of human CRC cells, and its involvement in amino acid and glutathione metabolism was demonstrated. In human CRC specimens, a decrease in C14orf159 expression at the invasive front of the tumour and in metastasis was determined. C14orf159 was also shown to attenuate the migration, invasion, and spheroid growth of CRC cells in vitro and colorectal tumour growth and metastasis in vivo. Mechanistically, C14orf159 reduced the expression of genes involved in CRC metastasis, including members of the Wnt and MMP family, by maintaining the mitochondrial membrane potential.

Conclusions

Our findings link mitochondrial membrane potential to Wnt/β-catenin signalling and reveal a previously unrecognised function of the mitochondrial matrix protein C14orf159 as a suppressor of CRC metastasis.

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Fig. 1: C14orf159 is localised in the mitochondrial matrix and maintains the mitochondrial membrane potential in human colorectal cancer cells.
Fig. 2: C14orf159 expression is downregulated in the invasion fronts and metastatic lesions of human colorectal adenocarcinoma.
Fig. 3: C14orf159 suppresses colorectal cancer cell migration and invasive capabilities in vitro.
Fig. 4: C14orf159 attenuates colorectal cancer spheroid growth in vitro.
Fig. 5: C14orf159 regulates the expression of genes involved in colorectal cancer metastasis.
Fig. 6: C14orf159 attenuates colorectal tumour growth and metastasis in vivo.

Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request. RNA-sequence data that support the findings of this study have been deposited in GEO with the accession code GSE167947. The previously published data of colorectal cancer cells that have been reanalysed here are available in GEO with the accession code GSE131418 [37]. Data in Fig. 2a are publicly available online at www.oncomine.org [36].

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Acknowledgements

We thank Mr. Masaharu Kohara, Ms. Etsuko Maeno and Ms. Takako Sawamura from the Department of Pathology, Osaka University Graduate School of Medicine, and this study was supported by Eiji Oiki, Tomoaki Mizuno and Center for Medical Research and Education, Osaka University Graduate School of Medicine.

Funding

This work was supported by JSPS KAKENHI Grant Number 20K16220 (KO), 19H03452 (EM) and the Takeda Science Foundation (KO).

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KO carried out most of the experiments, analysed data and managed clinical information. RO performed immunohistochemistry of C14orf159 in human colorectal adenocarcinoma specimens. DO performed RNA-seq and analysed the data. MS performed metabolome analysis by GC–MS. SN double-checked the tissue samples. KO designed the project and wrote the manuscript, and EM checked the manuscript and supervised the project.

Corresponding authors

Correspondence to Kenji Ohshima or Eiichi Morii.

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The authors declare no competing interests.

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All experimental protocols involving human specimens were approved by the Ethical Review Board of the Graduate School of Medicine, Osaka University (No. 15234-2), and were performed in accordance with the committee guidelines and regulations. All patients provided informed consent. The study was performed in accordance with the Declaration of Helsinki. The protocols used for all animal experiments in this study were approved by the Animal Research Committee of Osaka University, Japan (No. 30050002).

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Ohshima, K., Oi, R., Okuzaki, D. et al. Mitochondrial matrix protein C14orf159 attenuates colorectal cancer metastasis by suppressing Wnt/β-catenin signalling. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01582-9

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