SpringerLink
Log in

Urinary dipeptidase 1 and trefoil factor 1 are promising biomarkers for early diagnosis of colorectal cancer

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Currently utilized serum tumor markers and fecal immunochemical tests do not have sufficient diagnostic power for colorectal cancer (CRC) due to their low sensitivities. To establish non-invasive urinary protein biomarkers for early CRC diagnosis, we performed stepwise analyses employing urine samples from CRCs and healthy controls (HCs).

Methods

Among 474 urine samples, 363 age- and sex-matched participants (188 HCs, 175 stage 0–III CRCs) were randomly divided into discovery (16 HCs, 16 CRCs), training (110 HCs, 110 CRCs), and validation (62 HCs, 49 CRCs) cohorts.

Results

Of the 23 urinary protein candidates comprehensively identified from mass spectrometry in the discovery cohort, urinary levels of dipeptidase 1 (uDPEP1) and Trefoil factor1 (uTFF1) were the two most significant diagnostic biomarkers for CRC in both training and validation cohorts using enzyme-linked immunosorbent assays. A urinary biomarker panel comprising uDPEP1 and uTFF1 significantly distinguished CRCs from HCs, showing area under the curves of 0.825–0.956 for stage 0–III CRC and 0.792–0.852 for stage 0/I CRC. uDPEP1 and uTFF1 also significantly distinguished colorectal adenoma (CRA) patients from HCs, with uDPEP1 and uTFF1 increasing significantly in the order of HCs, CRA patients, and CRC patients. Moreover, expression levels of DPEP1 and TFF1 were also significantly higher in the serum and tumor tissues of CRC, compared to HCs and normal tissues, respectively.

Conclusions

This study established a promising and non-invasive urinary protein biomarker panel, which enables the early detection of CRC with high sensitivity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145–64.

    Article  PubMed  Google Scholar 

  3. Shaukat A, Mongin SJ, Geisser MS, et al. Long-term mortality after screening for colorectal cancer. N Engl J Med. 2013;369:1106–14.

    Article  CAS  PubMed  Google Scholar 

  4. Tao S, Haug U, Kuhn K, et al. Comparison and combination of blood-based inflammatory markers with faecal occult blood tests for non-invasive colorectal cancer screening. Br J Cancer. 2012;106:1424–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. **e YH, Gao QY, Cai GX, et al. Fecal clostridium symbiosum for noninvasive detection of early and advanced colorectal cancer: test and validation studies. EBioMedicine. 2017;25:32–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Niedermaier T, Tikk K, Gies A, et al. Sensitivity of fecal immunochemical test for colorectal cancer detection differs according to stage and location. Clin Gastroenterol Hepatol. 2020;18(2920–8):e6.

    Google Scholar 

  7. Thomas DS, Fourkala EO, Apostolidou S, et al. Evaluation of serum CEA, CYFRA21-1 and CA125 for the early detection of colorectal cancer using longitudinal preclinical samples. Br J Cancer. 2015;113:268–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhao M, Li M, Yang Y, et al. A comprehensive analysis and annotation of human normal urinary proteome. Sci Rep. 2017;7:3024.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Okuda Y, Shimura T, Iwasaki H, et al. Urinary microRNA biomarkers for detecting the presence of esophageal cancer. Sci Rep. 2021;11:8508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shimura T, Dagher A, Sachdev M, et al. Urinary ADAM12 and MMP-9/NGAL complex detect the presence of gastric cancer. Cancer Prev Res (Phila). 2015;8:240–8.

    Article  CAS  PubMed  Google Scholar 

  11. Shimura T, Ebi M, Yamada T, et al. Urinary kallikrein 10 predicts the incurability of gastric cancer. Oncotarget. 2017;8:29247–57.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Iwasaki H, Shimura T, Yamada T, et al. A novel urinary microRNA biomarker panel for detecting gastric cancer. J Gastroenterol. 2019;54:1061–9.

    Article  PubMed  Google Scholar 

  13. Shimura T, Dayde D, Wang H, et al. Novel urinary protein biomarker panel for early diagnosis of gastric cancer. Br J Cancer. 2020;123:1656–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Iwasaki H, Shimura T, Kitagawa M, et al. A novel urinary miRNA biomarker for early detection of colorectal cancer. Cancers (Basel). 2022;14:461.

    Article  CAS  PubMed  Google Scholar 

  15. Shimura T, Iwasaki H, Kitagawa M, et al. Urinary cysteine-rich protein 61 and trefoil factor 3 as diagnostic biomarkers for colorectal cancer. Transl Oncol. 2019;12:539–44.

    Article  PubMed  PubMed Central  Google Scholar 

  16. McShane LM, Altman DG, Sauerbrei W, et al. Reporting recommendations for tumor marker prognostic studies. J Clin Oncol. 2005;23:9067–72.

    Article  PubMed  Google Scholar 

  17. Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. Epidemiology. 2007;18:805–35.

    Article  PubMed  Google Scholar 

  18. Sobin LH, Gospodarowicz MK, Wittekind C, et al. TNM classification of malignant tumours. 7th ed. Chichester: Wiley-Blackwell; 2009.

    Google Scholar 

  19. Rappsilber J, Ishihama Y, Mann M. Stop and go extraction tips for matrix-assisted laser desorption/ionization, nanoelectrospray, and LC/MS sample pretreatment in proteomics. Anal Chem. 2003;75:663–70.

    Article  CAS  PubMed  Google Scholar 

  20. **n G, Wang M, Jiao LL, et al. Protein-to-creatinine ratio in spot urine samples as a predictor of quantitation of proteinuria. Clin Chim Acta. 2004;350:35–9.

    Article  CAS  PubMed  Google Scholar 

  21. Ward DG, Nyangoma S, Joy H, et al. Proteomic profiling of urine for the detection of colon cancer. Proteome Sci. 2008;6:19.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sun Y, Guo Z, Liu X, et al. Noninvasive urinary protein signatures associated with colorectal cancer diagnosis and metastasis. Nat Commun. 2022;13:2757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zeng C, Qi G, Shen Y, et al. DPEP1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ASCL2. Cancer Med. 2023;12:412–24.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang G, Schetter A, He P, et al. DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma. PLoS ONE. 2012;7:e31507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. McIver CM, Lloyd JM, Hewett PJ, et al. Dipeptidase 1: a candidate tumor-specific molecular marker in colorectal carcinoma. Cancer Lett. 2004;209:67–74.

    Article  CAS  PubMed  Google Scholar 

  26. Park SY, Lee SJ, Cho HJ, et al. Dehydropeptidase 1 promotes metastasis through regulation of E-cadherin expression in colon cancer. Oncotarget. 2016;7:9501–12.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Yajima S, Ishii M, Matsushita H, et al. Expression profiling of fecal colonocytes for RNA-based screening of colorectal cancer. Int J Oncol. 2007;31:1029–37.

    CAS  PubMed  Google Scholar 

  28. Liu Q, Deng J, Yang C, et al. DPEP1 promotes the proliferation of colon cancer cells via the DPEP1/MYC feedback loop regulation. Biochem Biophys Res Commun. 2020;532:520–7.

    Article  CAS  PubMed  Google Scholar 

  29. Yusufu A, Shayimu P, Tuerdi R, et al. TFF3 and TFF1 expression levels are elevated in colorectal cancer and promote the malignant behavior of colon cancer by activating the EMT process. Int J Oncol. 2019;55:789–804.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. **ao P, Ling H, Lan G, et al. Trefoil factors: Gastrointestinal-specific proteins associated with gastric cancer. Clin Chim Acta. 2015;450:127–34.

    Article  CAS  PubMed  Google Scholar 

  31. Rodrigues S, Rodrigue CM, Attoub S, et al. Induction of the adenoma-carcinoma progression and Cdc25A-B phosphatases by the trefoil factor TFF1 in human colon epithelial cells. Oncogene. 2006;25:6628–36.

    Article  CAS  PubMed  Google Scholar 

  32. Vocka M, Langer D, Petrtyl J, et al. Trefoil factor family (TFF) proteins as potential serum biomarkers in patients with metastatic colorectal cancer. Neoplasma. 2015;62:470–7.

    Article  CAS  PubMed  Google Scholar 

  33. Tokuhara T, Hattori N, Ishida H, et al. Clinical significance of aminopeptidase N in non-small cell lung cancer. Clin Cancer Res. 2006;12:3971–8.

    Article  CAS  PubMed  Google Scholar 

  34. Sanz B, Perez I, Beitia M, et al. Aminopeptidase N activity predicts 5-year survival in colorectal cancer patients. J Investig Med. 2015;63:740–6.

    Article  CAS  PubMed  Google Scholar 

  35. Wiese AH, Auer J, Lassmann S, et al. Identification of gene signatures for invasive colorectal tumor cells. Cancer Detect Prev. 2007;31:282–95.

    Article  CAS  PubMed  Google Scholar 

  36. Lu X, Pan J, Li S, et al. Establishment of a predictive genetic model for estimating chemotherapy sensitivity of colorectal cancer with synchronous liver metastasis. Cancer Biother Radiopharm. 2013;28:552–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Endo K, Kohnoe S, Tsujita E, et al. Galectin-3 expression is a potent prognostic marker in colorectal cancer. Anticancer Res. 2005;25:3117–21.

    CAS  PubMed  Google Scholar 

  38. Krijgsman D, Roelands J, Andersen MN, et al. Expression of NK cell receptor ligands in primary colorectal cancer tissue in relation to the phenotype of circulating NK- and NKT cells, and clinical outcome. Mol Immunol. 2020;128:205–18.

    Article  CAS  PubMed  Google Scholar 

  39. Rasmussen L, Nielsen HJ, Christensen IJ. Early detection and recurrence of colorectal adenomas by combination of eight cancer-associated biomarkers in plasma. Clin Exp Gastroenterol. 2020;13:273–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Mao Morimoto for supporting urinary analysis and Chiaki Tsuduki, Miki Shioya and Kana Saji for data management of enrolled patients in this study (Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences).

Funding

This study was funded, in part, by Japan Agency for Medical Research and Development (AMED) under Grant Number JP19lm0203005 (to T. S.), Grant-in-Aid for Research in Nagoya City University Grant Number 2021102 (to T. S.), and the Hori Science and Arts Foundation (to T. S.). The funder played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan

    Yusuke Okuda, Takaya Shimura, Hiroyasu Iwasaki, Ruriko Nishigaki, Shigeki Fukusada, Naomi Sugimura, Mika Kitagawa & Hiromi Kataoka

  2. Division of Molecular Diagnostics, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-Ku, Nagoya, Aichi, 464-8681, Japan

    Yuichi Abe & Ayumu Taguchi

  3. Okazaki Public Health Center, 1-3 Harusaki, Harisaki-Cho, Okazaki, 444-0827, Japan

    Tamaki Yamada

  4. Division of Advanced Cancer Diagnostics, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, Aichi, 466-8550, Japan

    Ayumu Taguchi

Authors
  1. Yusuke Okuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takaya Shimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuichi Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroyasu Iwasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ruriko Nishigaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shigeki Fukusada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naomi Sugimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mika Kitagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tamaki Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ayumu Taguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiromi Kataoka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takaya Shimura.

Ethics declarations

Conflict of interest

All authors declare no financial or non-financial competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 854 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okuda, Y., Shimura, T., Abe, Y. et al. Urinary dipeptidase 1 and trefoil factor 1 are promising biomarkers for early diagnosis of colorectal cancer. J Gastroenterol 59, 572–585 (2024). https://doi.org/10.1007/s00535-024-02110-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-024-02110-1

Keywords

Search

Navigation