Skip to main content

Advertisement

Log in

Dermokine as a novel biomarker for early-stage colorectal cancer

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

Abstract

Background

Colorectal cancer is a common disease that is usually detected at an advanced stage, because early-stage cancer is mostly asymptomatic and appropriate serologic biomarkers have not been established. We have previously identified dermokine (DK) as a peptide secreted by keratinocytes and we found that DK-β/γ was expressed in colorectal tumors. Therefore, we focused on DK-β/γ as a new candidate diagnostic serum marker for early colorectal cancer.

Methods

DK-β/γ expression in human colorectal cancer cell lines and tissues was assessed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. We established an experimental enzyme-linked immunosorbent assay (ELISA) to detect DK-β/γ in the serum of colorectal cancer patients, and we compared the sensitivities of common diagnostic markers, carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and serum p53 antibody (S-p53).

Results

Immunohistochemical staining of colon tumor tissue with anti-DK monoclonal antibody (mAb) revealed that DK-β/γ was more commonly expressed in the early stages of colorectal cancer (Tis–T1; i.e., cancer in situ, intraepithelial or invasion of lamina propria [Tis]; tumor invades the submucosa [T1]) than in late-stage tumors (T2–T4; i.e., tumor invades the muscularis propria [T2]; tumor invades through the muscularis propria into the subserosa, or into the nonperitonealized pericolic or perirectal tissues [T3]; tumor directly invades other organs or structures and/or perforates visceral peritoneum [T4]). Serum DK-β/γ levels were determined in 130 patients with colorectal cancer and 25 healthy volunteers. Serum DK-β/γ was detected in 33.3% of patients with early colorectal cancer (Tis–T1), which was higher than the rates for S-p53 (24.2%), CEA (9.1%), and CA19-9 (0%). The serum DK-β/γ test was complementary to the other marker tests. Therefore, when the combined four-marker test (DK/CEA/CA19-9/S-p53) was carried out, the diagnostic sensitivity for Tis and T1 tumors reached 60.6%.

Conclusions

Serum DK-β/γ is the most promising of the existing tumor biomarkers for the diagnosis of early-stage colorectal cancer.

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

Access this article

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
Fig. 5

Similar content being viewed by others

Abbreviations

DK:

Dermokine

CEA:

Carcinoembryonic antigen

CA19-9:

Carbohydrate antigen 19-9

S-p53:

Serum p53 antibody

ELISA:

Enzyme-linked immunosorbent assay

SSE:

Stratified squamous epithelium

Tis:

Cancer in situ, intraepithelial or invasion of lamina propria

T1:

Tumor invades the submucosa

T2:

Tumor invades the muscularis propria

T3:

Tumor invades through the muscularis propria into the subserosa, or into the nonperitonealized pericolic or perirectal tissues

T4:

Tumor directly invades other organs or structures and/or perforates visceral peritoneum. We followed the International Union Against Cancer (UICC) classification

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96.

    Article  PubMed  Google Scholar 

  2. Levin B, Lieberman DA, McFarland B, Smith RA, Brooks D, Andrews KS, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008;58:130–60.

    Article  PubMed  Google Scholar 

  3. Kuusela P, Jalanko H, Roberts P, Sipponen P, Mecklin JP, Pitkanen R, et al. Comparison of CA 19–9 and carcinoembryonic antigen (CEA) levels in the serum of patients with colorectal diseases. Br J Cancer. 1984;49:135–9.

    CAS  PubMed  Google Scholar 

  4. Zamcheck N, Pusztaszeri G. CEA, AFP and other potential tumor markers. CA Cancer J Clin. 1975;25:204–14.

    Article  CAS  PubMed  Google Scholar 

  5. Matsui T, Hayashi-Kisumi F, Kinoshita Y, Katahira S, Morita K, Miyachi Y, et al. Identification of novel keratinocyte-secreted peptides dermokine-alpha/-beta and a new stratified epithelium-secreted protein gene complex on human chromosome 19q13.1. Genomics. 2004;84:384–97.

    Article  CAS  PubMed  Google Scholar 

  6. Moffatt P, Salois P, St-Amant N, Gaumond MH, Lanctot C. Identification of a conserved cluster of skin-specific genes encoding secreted proteins. Gene. 2004;334:123–31.

    Article  CAS  PubMed  Google Scholar 

  7. Naso MF, Liang B, Huang CC, Song XY, Shahied-Arruda L, Belkowski SM, et al. Dermokine: an extensively differentially spliced gene expressed in epithelial cells. J Invest Dermatol. 2007;127:1622–31.

    CAS  PubMed  Google Scholar 

  8. Toulza E, Galliano MF, Jonca N, Gallinaro H, Mechin MC, Ishida-Yamamoto A, et al. The human dermokine gene: description of novel isoforms with different tissue-specific expression and subcellular location. J Invest Dermatol. 2006;126:503–6.

    Article  CAS  PubMed  Google Scholar 

  9. Tanami H, Tsuda H, Okabe S, Iwai T, Sugihara K, Imoto I, et al. Involvement of cyclin d3 in liver metastasis of colorectal cancer, revealed by genome-wide copy-number analysis. Lab Invest. 2005;85:1118–29.

    Article  CAS  PubMed  Google Scholar 

  10. Matsuda T, Fujii T, Saito Y, Nakajima T, Uraoka T, Kobayashi N, et al. Efficacy of the invasive/non-invasive pattern by magnifying chromoendoscopy to estimate the depth of invasion of early colorectal neoplasms. Am J Gastroenterol. 2008;103:2700–6.

    Article  PubMed  Google Scholar 

  11. Kudo S, Lambert R, Allen JI, Fujii H, Fujii T, Kashida H, et al. Nonpolypoid neoplastic lesions of the colorectal mucosa. Gastrointest Endosc. 2008;68:S3–47.

    Google Scholar 

  12. Bodmer WF. Cancer genetics: colorectal cancer as a model. J Hum Genet. 2006;51:391–6.

    Article  CAS  PubMed  Google Scholar 

  13. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87:159–70.

    Article  CAS  PubMed  Google Scholar 

  14. Kondo Y, Issa JP. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev. 2004;23:29–39.

    Article  CAS  PubMed  Google Scholar 

  15. Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med. 1965;122:467–81.

    Article  CAS  PubMed  Google Scholar 

  16. Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006;24:5313–27.

    Article  CAS  PubMed  Google Scholar 

  17. Koprowski H, Herlyn M, Steplewski Z, Sears HF. Specific antigen in serum of patients with colon carcinoma. Science. 1981;212:53–5.

    Article  CAS  PubMed  Google Scholar 

  18. Levine AJ. P53, the cellular gatekeeper for growth and division. Cell. 1997;88:323–31.

    Article  CAS  PubMed  Google Scholar 

  19. Sigal A, Rotter V. Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res. 2000;60:6788–93.

    CAS  PubMed  Google Scholar 

  20. Vousden KH. P53: death star. Cell. 2000;103:691–4.

    Article  CAS  PubMed  Google Scholar 

  21. Crawford LV, Pim DC, Bulbrook RD. Detection of antibodies against the cellular protein p53 in sera from patients with breast cancer. Int J Cancer. 1982;30:403–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We wish to thank Toshitaka Sato, Yasuyuki Honda, Yasunori Shimoduru, and Masahiko Katayama (Eisai Tsukuba Research Laboratories, Eisai Co., Ltd.) for technical assistance with ELISA, and Sayaka Katahira-Tayama and Itsumi Ohmori (MTT Program, Tokyo Medical and Dental University) for technical assistance with quantitative real time RT-PCR and immunoblotting; Satoru Yasukawa and Akio Yanagisawa (Department of Pathology, Kyoto Prefectural University of Medicine) for histopathological assistance; Toshikazu Yoshikawa and Nobuaki Yagi (Department of Medicine, Kyoto Prefectural University of Medicine) for kindly providing serum samples from patients with adenoma; and Shinzaburo Noguchi (Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Osaka, Japan), Nagahide Matsubara (Department of Surgery, Hyogo College of Medicine), and Tesshi Yamada (Chemotherapy Division and Cancer Proteomics Project, National Cancer Research Institute, Tokyo, Japan) for helpful discussions. This work was supported by a Grant-in-Aid for Scientific Research (C) 17591428, the Third-Term Comprehensive Control Research for Cancer conducted by the Ministry of Health, Labor and Welfare of Japan and the Charitable Trust Laboratory Medicine Foundation of Japan for Shojiro Kikuchi. This work was supported by a Grant-in-Aid for Young Scientists (Start-up) 19890118 for Takeshi Matsui and by the Program for Improvement of Research Environment for Young Researchers from the Special Coordination Funds for Promoting Science and Technology (SCF), commissioned by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan for Takeshi Matsui.

Conflict of interest statement

No potential conflicts of interest were disclosed.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shojiro Kikuchi.

Additional information

This work is dedicated to the memory of Shoichiro Tsukita.

T. Tagi and T. Matsui contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

535_2010_279_MOESM1_ESM.tif

Supplementary Fig. 1 Partial epitope mapping of anti-DK mAbs. One microgram of purified GST fusion proteins GST-hDK-β(22–167), GST-hDK-β(168–346) and GST-hDK-β(347–410) of DK-β were subjected to SDS-PAGE, stained with Coomassie Brilliant Blue (CBB) and immunoblotted with anti-DK mAb #45. The monoclonal Ab #45 exclusively recognized GST hDK-β(22–167), which indicates that its epitope is located between amino acids 22 and 167 of human DK-β; Ab #45 did not react with isoforms hDK-α, -ε or -δ (TIFF 2.91 mb)

535_2010_279_MOESM2_ESM.tif

Supplementary Fig. 2 ROC curve for DK(Tis-T1). Receiver-operator characteristic (ROC) curves for DK in separating normal healthy control and early-stage (Tis-T1) colorectal cancer patients. The area under curve was 67.0% (TIFF 1.48 mb)

535_2010_279_MOESM3_ESM.tif

Supplementary Table 1 Relationship between clinicopathological features and serum DK in colorectal cancer patients. The χ2 test was performed to determine correlations among the various parameters, and Fisher's exact test was used as appropriate. Results are expressed as means ± SD. Differences were considered significant when the two-tailed P was <0.05. Well, well-differentiated adenocarcinoma; pap, papillary adenocarcinoma; tubl, well-differentiated type; Mod, moderately differentiated adenocarcinoma; tub2,moderately differentiated type; Por, poorly differentiated adenocarcinoma (TIFF 121 kb)

535_2010_279_MOESM4_ESM.tif

Supplementary Table 2 The serum concentartion of DK, CAE, CA19-9 and S-p53in adenoma. The only one case showed high level of DK in adenoma, DK test did not include high false-positives in our data. We speculated that the expression of DK in adenoma did not affect serum concentration (TIFF 503 kb)

Supplementary Material and Methods (DOC 62 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tagi, T., Matsui, T., Kikuchi, S. et al. Dermokine as a novel biomarker for early-stage colorectal cancer. J Gastroenterol 45, 1201–1211 (2010). https://doi.org/10.1007/s00535-010-0279-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-010-0279-4

Keywords

Navigation