Article | Published:

Molecular Diagnostics

(Pro)renin receptor promotes colorectal cancer through the Wnt/beta-catenin signalling pathway despite constitutive pathway component mutations

British Journal of Cancer (2018) | Download Citation

Abstract

Background

Although constitutive activating mutations in the Wnt/β-catenin signalling pathway are important for colorectal cancer development, canonical signalling through Wnt ligands is essential for β-catenin activation. Here, we investigated the role of (pro)renin receptor ((P)RR), a component of the Wnt receptor complex, in the pathogenesis of colorectal cancer.

Methods

(P)RR silencing was performed in human colorectal cancer cells containing constitutive activating mutations in the Wnt/β-catenin pathway. (P)RR overexpression was induced in normal colon epithelial cells. Protein and mRNA levels of pathway components were detected, and Wnt signalling activity was measured using a β-catenin reporter. Cell proliferative activity and apoptosis were evaluated using WST-1 assay and flow cytometry. Xenografts were induced in nude mice.

Results

(P)RR expression was greater in colorectal cancer tissues and cells than in normal colorectal samples. Patients with strong (P)RR expression took more proportion in groups with poorly-differentiated, advanced and rapidly-progressing cancers. (P)RR silencing attenuated the pathway in colorectal cancer cells, impaired their proliferation in vitro and vivo. (P)RR overexpression enhanced the pathway and proliferation of normal colon epithelial cells.

Conclusions

Aberrant (P)RR expression promotes colorectal cancer through the Wnt/β-catenin signalling pathway despite constitutive pathway-activating mutations. (P)RR is a potential diagnostic and therapeutic target for colorectal cancer.

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Acknowledgements

We thank Mr. Kouichi Yuube (Division of Research Instrument and Equipment, Kagawa University) for technical assistance with flow cytometry. We thank Dr. Gabrielle White Wolf (Edanz Group) for polishing the language. We thank Miss Kanako Otsuki (Medical School of Kagawa University) for modifying the figure of schematic diagram. This work was supported by the Hoansha Foundation and Alumni Association of Kagawa University Medical School (Sanjukai).

Author information

Affiliations

  1. Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang Province, China

    • Juan Wang
  2. Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan

    • Juan Wang
    • , Yuki Shibayama
    • , Anqi Zhang
    •  & Akira Nishiyama
  3. Department of Immuno-oncology, Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei Province, China

    • Juan Wang
    •  & Zhiyu Wang
  4. Department of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, 650-0017, Japan

    • Hiroyuki Ohsaki
  5. Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan

    • Yasuyuki Suzuki
  6. Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan

    • Yoshio Kushida
  7. Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan

    • Hideki Kobara
    •  & Tsutomu Masaki

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Contributions

A.N., J.W. and Y.S. conceived and designed the research; J.W., A.Z. and H.O. performed the experiments; E.A., Y.S., Y.K., H.K. and T.M. enrolled patients’ tissue samples, analysed their pathological characteristics and collected patients’ clinical data; Y.K. reviewed clinical samples and confirmed the accuracy of diagnosis; J.W., Y.S., Z.W. and A.N. analysed all experimental and clinical data. J.W. wrote the manuscript; A.N., Y.S. and Z.W. supervised the study and revised the manuscript. All authors have read and approved the final manuscript.

Availability of data and materials

All data generated or analysed during this study are included in this article and its supplementary information files.

Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki. All protocols were approved by the Ethics Committee of Kagawa University. Colon tissue samples were obtained from Kagawa University Hospital. Informed consents were obtained from all the patients or their guardians. Experiments with animals were performed in accordance to the guidelines for experimental animal managements established by Kagawa University.

Conflict of interest

The authors declare that they have no conflict of interest.

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Corresponding author

Correspondence to Akira Nishiyama.

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DOI

https://doi.org/10.1038/s41416-018-0350-0