Exogenous DKK‑3/REIC inhibits Wnt/β‑catenin signaling and cell proliferation in human kidney cancer KPK1

Xu,Jiaqi; Sadahira,Takuya; Kinoshita,Rie; Li,Shun‑Ai; Huang,Peng; Wada,Koichiro; Araki,Motoo; Ochiai,Kazuhiko; Noguchi,Hirofumi; Sakaguchi,Masakiyo; Nasu,Yasutomo; Watanabe,Masami

doi:10.3892/ol.2017.6833

November-2017 Volume 14 Issue 5

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November-2017 Volume 14 Issue 5

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Article

Exogenous DKK‑3/REIC inhibits Wnt/β‑catenin signaling and cell proliferation in human kidney cancer KPK1

Authors:
- Jiaqi Xu
- Takuya Sadahira
- Rie Kinoshita
- Shun‑Ai Li
- Peng Huang
- Koichiro Wada
- Motoo Araki
- Kazuhiko Ochiai
- Hirofumi Noguchi
- Masakiyo Sakaguchi
- Yasutomo Nasu
- Masami Watanabe
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Affiliations: Department of Urology, Okayama University, Okayama 700‑8558, Japan, Cell Biology, Okayama University, Okayama 700‑8558, Japan, Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700‑8558, Japan, Department of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo 180‑0023, Japan, Department of Regenerative Medicine, University of The Ryukyus, Nishihara, Okinawa 903‑0213, Japan
Pages: 5638-5642
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Published online on: August 28, 2017

https://doi.org/10.3892/ol.2017.6833
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Abstract

The third member of the Dickkopf family (DKK‑3), also known as reduced expression in immortalized cells (REIC), is a tumor suppressor present in a variety of tumor cells. Regarding the regulation of the Wnt/β‑catenin signaling pathway, exogenous DKK‑1 and DKK‑2 are reported to inhibit Wnt signaling by binding the associated effectors. However, whether exogenous DKK‑3 inhibits Wnt signaling remains unclear. A recombinant protein of human full‑length DKK‑3 was used to investigate the exogenous effects of the protein in vitro in KPK1 human renal cell carcinoma cells. It was demonstrated that the expression of phosphorylated (p‑)β‑catenin (inactive form as the transcriptional factor) was increased in KPK1 cells treated with the exogenous DKK‑3 protein. The levels of non‑p‑β‑catenin (activated form of β‑catenin) were consistently decreased. It was revealed that the expression of transcription factor (TCF) 1 and c‑Myc, the downstream transcription factors of the Wnt/β‑catenin signaling pathway, was inhibited following treatment with DKK‑3. A cancer cell viability assay confirmed the anti‑proliferative effects of exogenous DKK‑3 protein, which was consistent with a suppressed Wnt/β‑catenin signaling cascade. In addition, as low‑density lipoprotein receptor‑related protein 6 (LRP6) is a receptor of DKK‑1 and DKK‑2 and their interaction on the cell surface inhibits Wnt/β‑catenin signaling, it was examined whether the exogenous DKK‑3 protein affects LRP6‑mediated Wnt/β‑catenin signaling. The LRP6 gene was silenced and the effects of DKK‑3 on the time course of the upregulation of p‑β‑catenin expression were subsequently analyzed. Notably, LRP6 depletion elevated the base level of p‑β‑catenin; however, there was no significant effect on its upregulation course or expression pattern. These findings indicate that exogenous DKK‑3 upregulates p‑β‑catenin and inhibits Wnt/β‑catenin signaling in an LRP6‑independent manner. Therefore, exogenous DKK‑3 protein may inhibit the proliferation of KPK1 cells via inactivating Wnt/β‑catenin signaling.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Exogenous DKK‑3/REIC inhibits Wnt/β‑catenin signaling and cell proliferation in human kidney cancer KPK1

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