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PRDM14 promotes malignant phenotype and correlates with poor prognosis in colorectal cancer

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Abstract

Background

Emerging evidence suggests that stemness in cancer cells is a cause of drug resistance or metastasis and is an important therapeutic target. PR [positive regulatory domain I-binding factor 1 (PRDI-BF1) and retinoblastoma protein-interacting zinc finger gene (RIZ1)] domain containing 14 (PRDM14), that regulates pluripotency in primordial germ cell, has reported the overexpression and function of stemness in various malignancies, suggesting it as the possible therapeutic target. However, to our knowledge, there have been no reports on the expression and function of PRDM14 in colorectal cancer (CRC). Therefore, we investigated the expression and the role of PRDM14 in CRC.

Methods

We performed immunohistochemistry evaluations and assessed PRDM14 expression on 414 primary CRC specimens. Colon cancer cell lines were subjected to functional and stemness assays in vitro and in vivo.

Results

We found that PRDM14 positive staining exhibited heterogeneity in the CRC primary tumor, especially at the tumor invasion front. The aberrant expression of PRDM14 at the invasion front was associated with lymph node metastasis and disease stage in patients with CRC. Furthermore, the multivariate analysis revealed high PRDM14 expression as an independent prognostic factor in the patients with Stage III CRC. Overexpression of PRDM14 enhanced the invasive, drug-resistant and stem-like properties in colon cancer cells in vitro and tumorigenicity in vivo.

Conclusion

Our findings suggest that PRDM14 is involved in progression and chemoresistance of CRC, and is a potential prognostic biomarker and therapeutic target in the CRC patients.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ALDH:

Aldehyde dehydrogenase

CI:

Confidence interval

CRC:

Colorectal cancer

ESC:

Embryonic stem cell

FFPE:

Formalin-fixed, paraffin-embedded

HR:

Hazard ratio

IHC:

Immunohistochemistry

PGC:

Primordial germ cell

PRDM14:

Positive regulatory domain I-binding factor 1 and retinoblastoma protein-interacting zinc finger gene 1 domain containing 14

qRT-PCR:

Quantitative reverse transcription PCR

SD:

Standard deviation

TIF:

Tumor invasion front

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Acknowledgements

We thank the pathology departments of Sapporo Medical University Hospital and Keiyukai Sapporo Hospital for providing the tissue specimens. Writing assistance: the authors would like to thank Enago (https://www.enago.jp) for English language review.

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (Grant number 26860515 to H. I.), Takeda Science Foundation (to H. I.), Daiwa Securities Health Foundation (to H. I.), JSPS Grant-in-Aid for Scientific Research (Grant number 16K07145 to K. N.), and Japan Agency for Medical Research and Development (Grant number 16Ack0106108h0003 to H. T.). The funding bodies had no involvement in the design of the study, collection, analysis, and interpretation of data and in writing the manuscript.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chou-ku, Sapporo, 060-8543, Japan

    H. Igarashi, K. Nosho, K. Ishigami, H. Koide, K. Mitsuhashi & H. Nakase

  2. The Center for Antibody and Vaccine Therapy, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    H. Taniguchi

  3. Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan

    K. Okita & I. Takemasa

  4. The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    K. Imai

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  1. H. Igarashi
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Contributions

Study concept and design: HI, HT. Data acquisition: HI, KI1, HK, KM, KO, IT. Data analysis and interpretation: HI, HT, KN. Drafting of the manuscript: HI, KI1, HK, KM. Critical revision of the manuscript for important intellectual content: HT, KN, KO, IT, KI2, HN. Statistical analysis: HI. Final approval of manuscript: all authors.

Corresponding author

Correspondence to H. Igarashi.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

This study was approved by the institutional review board of Sapporo Medical University Clinical trial center (reference number: 23-16), and was in accordance with the World Medical Association’s Declaration of Helsinki (1964, and its later amendments). All the animal studies were performed under the supervision of the Committee for Animal Research Center of Sapporo Medical University and in accordance with protocols approved by the Institutional Animal Care and Use Committee (reference number: 18-071).

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Igarashi, H., Taniguchi, H., Nosho, K. et al. PRDM14 promotes malignant phenotype and correlates with poor prognosis in colorectal cancer. Clin Transl Oncol 22, 1126–1137 (2020). https://doi.org/10.1007/s12094-019-02239-z

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