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Olfactomedin 4 produces dysplasia but suppresses metastasis of colon cancer

Cancer Gene Therapy volume 30, pages 694–703 (2023)Cite this article

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Abstract

Development of colorectal cancer (CRC) is regulated by a series of genetic and microenvironmental alterations. Olfactomedin 4 (OLFM4) is a secreted glycoprotein that is highly expressed in the gastrointestinal tract and modulates inflammation. However, the role of OLFM4 in CRC is uncertain. Here we aimed to explore the function of OLFM4 in CRC in vivo and in vitro. The mRNA expression of OLFM4 was up-regulated in precursor lesions with dysplasia or ulcerative colitis but was reduced in CRC. OLFM4 neutralizing antibody suppressed inflammation-mediated early-stage CRC formation in an AOM/DSS colitis-associated cancer model. OLFM4 knockdown cells exhibited increased cell proliferation and motility in vitro and in vivo. Ablation of OLFM4 increased tumor growth and metastasis in xenograft experiments. In addition, OLFM4 knockdown cells showed elevated expression of colon cancer stem cell markers including CD133, resulting in increased metastasis via epithelial-mesenchymal transition signaling. This study demonstrated that OLFM4 regulates inflammation and cancer progression differently; ablation of OLFM4 promotes cancer metastasis via stemness and epithelial-mesenchymal transition. These results suggest a new route for controlling cancer progression and metastasis.

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Fig. 1: OLFM4 expression is up-regulated in dysplasia and inflamed lesions but down-regulated in colorectal cancer progression.
Fig. 2: OLFM4 neutralizing antibody suppresses inflammation-mediated early-stage colon tumor formation in the AOM/DSS CAC model.
Fig. 3: OLFM4-positive immune cells are reduced by anti-OLFM4.
Fig. 4: OLFM4 depletion increases colon cancer cell proliferation in vitro and in vivo.
Fig. 5: The OLFM4 knockdown cell line shows increased cancer stem cell marker expression.
Fig. 6: OLFM4 neutralizing antibody inhibits metastatic nodule formation.
Fig. 7: OLFM4 ablation promotes cancer cell invasion.
Fig. 8: OLFM4 ablation promotes the epithelial-mesenchymal transition by inflammation.

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Data availability

The data generated in this study are available within the article and Supplementary Data.

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Acknowledgements

This work was supported by the Korean Gastroenterology Fund for Future Development and by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2020R1A2C1005322). We would like to thank the donors for their contribution to this study.

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  1. These authors contributed equally: Jae Hee Cheon, Seung Won Kim.

Authors and Affiliations

  1. Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea

    Hyun Woo Ma, I Seul Park, Ji Hyung Kim, Dong Hyuk Seo, Jae Hyeon Kim, Xiumei Che, Tae Il Kim, Jae Hee Cheon & Seung Won Kim

  2. Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea

    Jung Min Kim & Da Hye Kim

  3. Department of Surgery, Yonsei University College of Medicine, Seoul, Korea

    Ki Cheong Park

  4. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea

    Jae Hee Cheon & Seung Won Kim

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Contributions

HWM, SWK, and JHC designed the study; HWM, KCP, and SWK performed experiments; HWM and SWK were involved in data analysis; HWM, DHK, JMK, ISP, JHK, DHS, JHK, XC, and TIK were involved in sample acquisition; JHC and SWK were involved in funding acquisition; HWM, SWK, and JHC wrote the manuscript. All authors contributed to critical revision of the manuscript and approved the final version.

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Correspondence to Jae Hee Cheon or Seung Won Kim.

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Ma, H.W., Kim, J.M., Kim, D.H. et al. Olfactomedin 4 produces dysplasia but suppresses metastasis of colon cancer. Cancer Gene Ther 30, 694–703 (2023). https://doi.org/10.1038/s41417-022-00585-9

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