Skip to main content

Advertisement

SpringerLink
Log in

Cartilage oligomeric matrix protein is a prognostic factor and biomarker of colon cancer and promotes cell proliferation by activating the Akt pathway

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Recent studies have determined that cartilage oligomeric matrix protein (COMP) plays a vital role in carcinogenesis. We sought to clarify the role of COMP in colon cancer.

Methods

We investigated gene expression data from The Cancer Genome Atlas (TCGA) dataset. Tissue microarrays (TMA) containing paired samples from 253 patients with colon cancer were subjected to immunostaining. COMP levels in serum of colon cancer patients and healthy donors were measured with ELISA. We established COMP-knockout cells using the CRISPR/Cas9 system and COMP-overexpressing cells using lentiviral vectors to detect the effects of COMP on colon cancer cells using Cell Counting Kit-8 (CCK8), colony formation, apoptosis detection kit, and tumorigenesis assays in nude mice.

Results

The analysis of TCGA dataset and the results of the TMA suggested that COMP expression levels were significantly higher in cancer tissues than in adjacent normal tissues. Moreover, high COMP expression was correlated with the poor outcome of colon cancer patients. COMP levels in the sera of preoperative patients with colon cancer were much higher than those in healthy donors and were significantly reduced after colectomy. Colon cancer cells without COMP were defective with respect to the ability to proliferate, colony formation, the ability to resist 5-Fluorouracil-induced apoptosis and the growth of xenograft tumors in mice. Contrasting results were observed in COMP overexpressed cells. COMP promoted colon cancer cell proliferation partially through the activation of PI3K/ Akt/ mTOR/ p70S6K pathway.

Conclusions

COMP may be a novel prognostic indicator and biomarker and also a potential therapeutic target for colon cancer.

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

Access this article

Log in via an institution

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Bachmann IM, Puntervoll HE, Otte AP, Akslen LA (2008) Loss of BMI-1 expression is associated with clinical progress of malignant melanoma. Mod Pathol 21:583

    Article  CAS  PubMed  Google Scholar 

  • Bellacosa A et al (1998) Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 17:313

    Article  CAS  PubMed  Google Scholar 

  • Binello E, Germano IM (2011) Targeting glioma stem cells: a novel framework for brain tumors. Cancer Sci 102:1958–1966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Briggs M et al (1995) Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat Genet 10:330–336

    Article  CAS  PubMed  Google Scholar 

  • Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM (1998) RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 95:1432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Canman CE, Tang H-Y, Normolle DP, Lawrence TS, Maybaum J (1992) Variations in patterns of DNA damage induced in human colorectal tumor cells by 5-fluorodeoxyuridine: implications for mechanisms of resistance and cytotoxicity. Proc Natl Acad Sci 89:10474–10478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen W et al (2016) Cancer statistics in China, 2015 CA Cancer. J Clin 66:115–132. https://doi.org/10.3322/caac.21338

    Google Scholar 

  • Cho DY, Chen CC, Lee WY, Lee HC, Ho LH (2008) A new Modified Intracerebral Hemorrhage score for treatment decisions in basal ganglia hemorrhage—a randomized trial. Crit Care Med 36:2151

    Article  PubMed  Google Scholar 

  • Englund E et al (2016) Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer. Oncogene 35:5585–5596. https://doi.org/10.1038/onc.2016.98

    Article  CAS  PubMed  Google Scholar 

  • Farina G, Lemaire R, Korn JH, Widom RL (2006) Cartilage oligomeric matrix protein is overexpressed by scleroderma dermal fibroblasts. Matrix Biol 25:213–222. https://doi.org/10.1016/j.matbio.2006.01.007

    Article  CAS  PubMed  Google Scholar 

  • Guertin DA, Sabatini MD (2007) Defining the Role of mTOR in cancer. Cancer Cell 12:9

    Article  CAS  PubMed  Google Scholar 

  • Hecht JT et al (1995) Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nature Genet 10:325–329

    Article  CAS  PubMed  Google Scholar 

  • Kleinman MS, Turner MD (1972) Radioimmunoassay of carcinoembryonic antigen in serum of normal subjects and patients with colonic carcinoma. Gut 13:390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu X et al (2016) Breast cancer metastasis suppressor 1 modulates SIRT1-dependent p53 deacetylation through interacting with DBC1. Am J Cancer Res 6:1441

    CAS  PubMed  PubMed Central  Google Scholar 

  • Luo X et al (2015) Poly(ADP-ribosyl)ation of FOXP3 protein mediated by PARP-1 protein regulates the function of regulatory T cells. J Biol Chem 290:28675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayer IA, Arteaga CL (2015) The PI3K/AKT pathway as a target for cancer treatment. Ann Rev Med 67:11

    Article  PubMed  Google Scholar 

  • Neidhart M, Hauser N, Paulsson M, Dicesare PE, Michel BA, Häuselmann HJ (1997) Small fragments of cartilage oligomeric matrix protein in synovial fluid and serum as markers for cartilage degradation. Br J Rheumatol 36:1151

    Article  CAS  PubMed  Google Scholar 

  • Nita ME et al (1998) 5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins. Br J Cancer 78:986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Connell JB, Maggard MA, Ko CY (2004) Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 96:1420–1425

    Article  PubMed  Google Scholar 

  • Okano J, Gaslightwala I, Birnbaum MJ, Rustgi AK, Nakagawa H (2000) Akt/protein kinase B isoforms are differentially regulated by epidermal growth factor stimulation. J Biol Chem 275:30934–30942

    Article  CAS  PubMed  Google Scholar 

  • Oldberg A, Antonsson P, Lindblom K, Heinegård D (1992) COMP (cartilage oligomeric matrix protein) is structurally related to the thrombospondins. J Biol Chem 267:22346–22350

    CAS  PubMed  Google Scholar 

  • Piróg-Garcia KA et al (2007) Reduced cell proliferation and increased apoptosis are significant pathological mechanisms in a murine model of mild pseudoachondroplasia resulting from a mutation in the C-terminal domain of COMP. Hum Mol Genet 16:2072–2088

    Article  PubMed  PubMed Central  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098

    Article  CAS  PubMed  Google Scholar 

  • Saxne T, Heinegård D (1992) Cartilage oligomeric matrix protein: a novel marker of cartilage turnover detectable in synovial fluid and blood. Br J Rheumatol 31:583

    Article  CAS  PubMed  Google Scholar 

  • Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63:11–30. https://doi.org/10.3322/caac.21166

    Article  PubMed  Google Scholar 

  • Wick MJ, Dong LQ, Riojas RA, Ramos FJ, Liu F (2000) Mechanism of phosphorylation of protein kinase B/Akt by a constitutively active 3-phosphoinositide-dependent protein kinase-1. J Biol Chem 275:40400–40406

    Article  CAS  PubMed  Google Scholar 

  • Yakabe T et al (2010) Clinical significance of CEA and CA19-9 in postoperative follow-up of colorectal cancer. Ann Surg Oncol 17:2349–2356

    Article  PubMed  Google Scholar 

  • Yan D et al (2010) Ubiquitin D is correlated with colon cancer progression and predicts recurrence for stage II-III disease after curative surgery. Br J Cancer 103:961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yonemura Y, Ohoyama S, Kimura H, Kamata T, Yamaguchi A, Miyazaki I (1990) Assessment of tumor cell kinetics by monoclonal antibody Ki-67. Eur Surg Res 22:365–370

    Article  CAS  PubMed  Google Scholar 

  • Zachou K, Gabeta S, Shums Z, Gatselis NK, Koukoulis GK, Norman GL, Dalekos GN (2017) COMP serum levels: a new non-invasive biomarker of liver fibrosis in patients with chronic viral hepatitis. Eur J Intern Med 38:83–88. https://doi.org/10.1016/j.ejim.2017.01.007

    Article  CAS  PubMed  Google Scholar 

  • Zhang S, Cui Y, Weng Z, Gong X, Chen M, Zhong B (2009) Changes on the disease pattern of primary colorectal cancers in Southern China: a retrospective study of 20 years. Int J Colorectal Dis 24:943–949

    Article  PubMed  Google Scholar 

  • Zhang M et al (2015) Developmental pluripotency-associated 4: a novel predictor for prognosis and a potential therapeutic target for colon cancer. J Exp Clin Cancer Res 34:1–11

    Article  Google Scholar 

Download references

Acknowledgements

This Project was supported by the fund: National Natural Science Foundation of China (81472238).

Funding

This study was funded by National Natural Science Foundation of China (81472238).

Author information

Author notes

  1. Ting-ting Liu, Xi-sheng Liu, and Meng Zhang contributed equally.

Authors and Affiliations

  1. Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 85 Wujin Road, Shanghai, 200080, China

    Ting-ting Liu, Hui-min Sun, Su Lu, Yu Zhang, Jun Lin & Hua-mei Tang

  2. Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 85 Wujin Road, Shanghai, 200080, China

    Xi-sheng Liu, Xue-ni Liu, Si-wen Ouyang, Shan-bao Li, Chen-long Song & Zhi-hai Peng

  3. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China

    Meng Zhang

  4. Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, China

    Meng Zhang

  5. CAS Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, 200025, China

    Fu-xiang Zhu

  6. Shanghai Key laboratory of Bio-energy Crops, School of Life Science, Shanghai University, Shanghai, 200025, China

    Fang-ming Zhu

  7. Department of Pathology, Xiang’an Hospital, Xiamen University Medical College, Xiamen, 361101, Fujian, China

    Hua-mei Tang

Authors
  1. Ting-ting Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xi-sheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xue-ni Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fu-xiang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fang-ming Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Si-wen Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shan-bao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chen-long Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hui-min Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Su Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jun Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hua-mei Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Zhi-hai Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hua-mei Tang or Zhi-hai Peng.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All procedures performed in studies involving animals were in accordance with the ethical standards of the Shanghai General Hospital Animal Care guidelines. We have received an approval number 2014KY046 for this research project from the medical ethics committee of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 23 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Tt., Liu, Xs., Zhang, M. et al. Cartilage oligomeric matrix protein is a prognostic factor and biomarker of colon cancer and promotes cell proliferation by activating the Akt pathway. J Cancer Res Clin Oncol 144, 1049–1063 (2018). https://doi.org/10.1007/s00432-018-2626-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-018-2626-4

Keywords

Search

Navigation