Molecular Diagnostics

Syntenin-1 promotes colorectal cancer stem cell expansion and chemoresistance by regulating prostaglandin E2 receptor

Abstract

Background

The protein syntenin-1 is expressed by a variety of cell types, and is upregulated in various malignancies, including melanoma, breast cancer and glioma. Although the mechanism by which elevated syntenin-1 expression contributes to cancer has been described, the exact pathway has not been elucidated.

Methods

To investigate the involvement of syntenin-1 in colorectal cancer (CRC), we performed immunohistochemical analysis of 139 CRC surgical specimens. We also examined syntenin-1 knockdown in CRC cell lines.

Results

High syntenin-1 expression was associated with less differentiated histologic grade and poor prognosis, and was an independent prognostic indicator in CRC. Syntenin-1 knockdown in CRC cells reduced the presence of cancer stem cells (CSCs), oxaliplatin chemoresistance and migration. DNA microarray analysis and quantitative real-time polymerase chain reaction showed decreased prostaglandin E2 receptor 2 (PTGER2) expression in syntenin-1-knockdown cells. PTGER2 knockdown in CRC cells yielded the same phenotype as syntenin-1 knockdown. Celecoxib, which has anti-inflammatory effects by targeting cyclooxygenase-2, reduced CSCs and decreased chemoresistance, while prostaglandin E2 (PGE2) had the opposite effect.

Conclusions

Our findings suggested that syntenin-1 enhanced CSC expansion, oxaliplatin chemoresistance and migration capability through regulation of PTGER2 expression. Syntenin-1 may be a promising new prognostic factor and target for anti-cancer therapies.

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Fig. 1: Syntenin-1 expression is associated with cancer.
Fig. 2: Syntenin-1 is associated with the malignant potential of cancer.
Fig. 3: Syntenin-1 expression is associated with prostaglandin E2 receptor 2 (EP2) expression.
Fig. 4: Coexistence of EP2 and syntenin-1 is associated with L-OHP chemosensitivity and sphere formation of cancer.
Fig. 5: Kaplan–Meier curves for OS or RFS according to syntenin-1 expression.

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Acknowledgements

We thank the Center for Medical Research and Education, Graduate School of Medicine, Osaka University for technical assistance. We are grateful to Makoto Fujii, Ph.D. (Department of Mathematical Health Science, Osaka University Graduate School of Medicine Division of Health Sciences) for statistical evaluation.

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Authors

Contributions

K.I. and H.T. contributed to the study conception and design and wrote this manuscript. D.O. contributed to the data analysis and interpretation and provided a method for IPA. H.O., T.O., N.M., M.U., C.M., H.Y. and T.M. contributed to the data acquisition, and critical evaluation of the results. M.M., Y.D. and H.E. supervised the entire research project, including proofreading and final confirmation of the manuscript.

Corresponding author

Correspondence to Hidekazu Takahashi.

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Ethics approval and consent to participate

All experimental protocols described in this study were approved by the Institutional Ethical Review Committee (UMIN 15046-3: comprehensive agreement) and conform to the provisions of the Declaration of Helsinki. All patients provided written informed consent.

Data availability

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

Competing interests

The authors declare no competing interests.

Funding information

The present study was supported by JSPS KAKENHI Grant Numbers 18K16357 and 18K08678.

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Iwamoto, K., Takahashi, H., Okuzaki, D. et al. Syntenin-1 promotes colorectal cancer stem cell expansion and chemoresistance by regulating prostaglandin E2 receptor. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-0965-9

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