Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
June-2015 Volume 33 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
June-2015 Volume 33 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression

  • Authors:
    • Rie Kinoshita
    • Masami Watanabe
    • Peng Huang
    • Shun-Ai Li
    • Masakiyo Sakaguchi
    • Hiromi Kumon
    • Junichiro Futami
  • View Affiliations / Copyright

    Affiliations: Department of Biotechnology, Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan, Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan, Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University, Okayama, Japan, Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
  • Pages: 2908-2914
    |
    Published online on: March 30, 2015
       https://doi.org/10.3892/or.2015.3885
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor-suppressor gene and has been studied as a promising therapeutic gene for cancer gene therapy. Intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) elicits cancer cell‑specific apoptosis and anticancer immune responses. The cytokine-like effect of secretory REIC/Dkk-3 on the induction of dendritic cell (DC)-like cell differentiation from monocytes plays a role in systemic anticancer immunity. In the present study, we generated recombinant full-length and N-terminally truncated REIC/Dkk-3 to characterize the biological activity of the protein. During the purification procedure, we identified a 17 kDa cysteine-rich stable product (C17-REIC) showing limited degradation. Further analysis showed that the C17-REIC domain was sufficient for the induction of DC-like cell differentiation from monocytes. Concomitant with the differentiation of DCs, the REIC/Dkk-3 protein induced the phosphorylation of glycogen synthase kinase 3β (GSK-3β) and signal transducers and activators of transcription (STAT) at a level comparable to that of granulocyte/macrophage colony‑stimulating factor. In a mouse model of subcutaneous renal adenocarcinoma, intraperitoneal injection of full-length and C17-REIC proteins exerted anticancer effects in parallel with the activation of immunocompetent cells such as DCs and cytotoxic T lymphocytes in peripheral blood. Taken together, our results indicate that the stable cysteine-rich core region of REIC/Dkk-3 is responsible for the induction of anticancer immune responses. Because REIC/Dkk-3 is a naturally circulating serum protein, the upregulation REIC/Dkk-3 protein expression could be a promising option for cancer therapy.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Krupnik VE, Sharp JD, Jiang C, et al: Functional and structural diversity of the human Dickkopf gene family. Gene. 238:301–313. 1999. View Article : Google Scholar : PubMed/NCBI

2 

Niehrs C: Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene. 25:7469–7481. 2006. View Article : Google Scholar : PubMed/NCBI

3 

Mao B, Wu W, Li Y, et al: LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature. 411:321–325. 2001. View Article : Google Scholar : PubMed/NCBI

4 

Li L, Mao J, Sun L, Liu W and Wu D: Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled. J Biol Chem. 277:5977–5981. 2002. View Article : Google Scholar

5 

Cheng Z, Biechele T, Wei Z, et al: Crystal structures of the extracellular domain of LRP6 and its complex with DKK1. Nat Struct Mol Biol. 18:1204–1210. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Nakamura RE and Hackam AS: Analysis of Dickkopf3 interactions with Wnt signaling receptors. Growth Factors. 28:232–242. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Fujii Y, Hoshino T and Kumon H: Molecular simulation analysis of the structure complex of C2 domains of DKK family members and β-propeller domains of LRP5/6: explaining why DKK3 does not bind to LRP5/6. Acta Med Okayama. 68:63–78. 2014.

8 

Fujita K and Janz S: Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF. Mol Cancer. 6:712007. View Article : Google Scholar : PubMed/NCBI

9 

Tsuji T, Miyazaki M, Sakaguchi M, Inoue Y and Namba M: A REIC gene shows down-regulation in human immortalized cells and human tumor-derived cell lines. Biochem Biophys Res Commun. 268:20–24. 2000. View Article : Google Scholar : PubMed/NCBI

10 

Tsuji T, Nozaki I, Miyazaki M, et al: Antiproliferative activity of REIC/Dkk-3 and its significant down-regulation in non-small-cell lung carcinomas. Biochem Biophys Res Commun. 289:257–263. 2001. View Article : Google Scholar : PubMed/NCBI

11 

Abarzua F, Sakaguchi M, Takaishi M, et al: Adenovirus-mediated overexpression of REIC/Dkk-3 selectively induces apoptosis in human prostate cancer cells through activation of c-Jun-NH2-kinase. Cancer Res. 65:9617–9622. 2005. View Article : Google Scholar : PubMed/NCBI

12 

Tanimoto R, Abarzua F, Sakaguchi M, et al: REIC/Dkk-3 as a potential gene therapeutic agent against human testicular cancer. Int J Mol Med. 19:363–368. 2007.PubMed/NCBI

13 

Shien K, Tanaka N, Watanabe M, et al: Anti-cancer effects of REIC/Dkk-3-encoding adenoviral vector for the treatment of non-small cell lung cancer. PLoS One. 9:e879002014. View Article : Google Scholar : PubMed/NCBI

14 

Hirata T, Watanabe M, Kaku H, et al: REIC/Dkk-3-encoding adenoviral vector as a potentially effective therapeutic agent for bladder cancer. Int J Oncol. 41:559–564. 2012.PubMed/NCBI

15 

Than SS, Kataoka K, Sakaguchi M, et al: Intraperitoneal administration of an adenovirus vector carrying REIC/Dkk-3 suppresses peritoneal dissemination of scirrhous gastric carcinoma. Oncol Rep. 25:989–995. 2011.PubMed/NCBI

16 

Uchida D, Shiraha H, Kato H, et al: Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer. J Gastroenterol Hepatol. 29:973–983. 2014. View Article : Google Scholar : PubMed/NCBI

17 

Sakaguchi M, Kataoka K, Abarzua F, et al: Overexpression of REIC/Dkk-3 in normal fibroblasts suppresses tumor growth via induction of interleukin-7. J Biol Chem. 284:14236–14244. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Tanimoto R, Sakaguchi M, Abarzua F, et al: Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk-3. Int J Cancer. 126:1562–1569. 2010.

19 

Abarzua F, Kashiwakura Y, Takaoka M, et al: An N-terminal 78 amino acid truncation of REIC/Dkk-3 effectively induces apoptosis. Biochem Biophys Res Commun. 375:614–618. 2008. View Article : Google Scholar : PubMed/NCBI

20 

Watanabe M, Nasu Y and Kumon H: Adenovirus-mediated REIC/Dkk-3 gene therapy: Development of an autologous cancer vaccination therapy (Review). Oncol Lett. 7:595–601. 2014.PubMed/NCBI

21 

Watanabe M, Kashiwakura Y, Huang P, et al: Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression. Int J Oncol. 34:657–663. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Zou GM and Tam YK: Cytokines in the generation and maturation of dendritic cells: recent advances. Eur Cytokine Netw. 13:186–199. 2002.PubMed/NCBI

23 

Conti L and Gessani S: GM-CSF in the generation of dendritic cells from human blood monocyte precursors: Recent advances. Immunobiology. 213:859–870. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Schuler G, Schuler-Thurner B and Steinman RM: The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol. 15:138–147. 2003. View Article : Google Scholar : PubMed/NCBI

25 

Nestle FO: Dendritic cell vaccination for cancer therapy. Oncogene. 19:6673–6679. 2000. View Article : Google Scholar

26 

Zenzmaier C, Sklepos L and Berger P: Increase of Dkk-3 blood plasma levels in the elderly. Exp Gerontol. 43:867–870. 2008. View Article : Google Scholar : PubMed/NCBI

27 

Sakaguchi M, Watanabe M, Kinoshita R, et al: Dramatic increase in expression of a transgene by insertion of promoters downstream of the cargo gene. Mol Biotechnol. 56:621–630. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Watanabe M, Sakaguchi M, Kinoshita R, et al: A novel gene expression system strongly enhances the anticancer effects of a REIC/Dkk-3-encoding adenoviral vector. Oncol Rep. 31:1089–1095. 2014.PubMed/NCBI

29 

van de Laar L, Coffer PJ and Woltman AM: Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy. Blood. 119:3383–3393. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Laouar Y, Welte T, Fu XY and Flavell RA: STAT3 is required for Flt3L-dependent dendritic cell differentiation. Immunity. 19:903–912. 2003. View Article : Google Scholar : PubMed/NCBI

31 

Tormo AJ and Gauchat JF: A novel role for STAT5 in DC: Controlling the Th2-response. JAKSTAT. 2:e253522013.

32 

Alessandrini A, De Haseth S, Fray M, et al: Dendritic cell maturation occurs through the inhibition of GSK-3β. Cell Immunol. 270:114–125. 2011. View Article : Google Scholar

33 

Vilimek D and Duronio V: Cytokine-stimulated phosphorylation of GSK-3 is primarily dependent upon PKCs, not PKB. Biochem Cell Biol. 84:20–29. 2006. View Article : Google Scholar : PubMed/NCBI

34 

Luo J: Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. Cancer Lett. 273:194–200. 2009. View Article : Google Scholar

35 

Ochiai K, Watanabe M, Ueki H, et al: Tumor suppressor REIC/Dkk-3 interacts with the dynein light chain, Tctex-1. Biochem Biophys Res Commun. 412:391–395. 2011. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Kinoshita R, Watanabe M, Huang P, Li S, Sakaguchi M, Kumon H and Futami J: The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression. Oncol Rep 33: 2908-2914, 2015.
APA
Kinoshita, R., Watanabe, M., Huang, P., Li, S., Sakaguchi, M., Kumon, H., & Futami, J. (2015). The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression. Oncology Reports, 33, 2908-2914. https://doi.org/10.3892/or.2015.3885
MLA
Kinoshita, R., Watanabe, M., Huang, P., Li, S., Sakaguchi, M., Kumon, H., Futami, J."The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression". Oncology Reports 33.6 (2015): 2908-2914.
Chicago
Kinoshita, R., Watanabe, M., Huang, P., Li, S., Sakaguchi, M., Kumon, H., Futami, J."The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression". Oncology Reports 33, no. 6 (2015): 2908-2914. https://doi.org/10.3892/or.2015.3885
Copy and paste a formatted citation
x
Spandidos Publications style
Kinoshita R, Watanabe M, Huang P, Li S, Sakaguchi M, Kumon H and Futami J: The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression. Oncol Rep 33: 2908-2914, 2015.
APA
Kinoshita, R., Watanabe, M., Huang, P., Li, S., Sakaguchi, M., Kumon, H., & Futami, J. (2015). The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression. Oncology Reports, 33, 2908-2914. https://doi.org/10.3892/or.2015.3885
MLA
Kinoshita, R., Watanabe, M., Huang, P., Li, S., Sakaguchi, M., Kumon, H., Futami, J."The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression". Oncology Reports 33.6 (2015): 2908-2914.
Chicago
Kinoshita, R., Watanabe, M., Huang, P., Li, S., Sakaguchi, M., Kumon, H., Futami, J."The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression". Oncology Reports 33, no. 6 (2015): 2908-2914. https://doi.org/10.3892/or.2015.3885
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team