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

  • Published online on: March 30, 2015     https://doi.org/10.3892/or.2015.3885
  • Pages: 2908-2914
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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.
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June-2015
Volume 33 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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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