DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells. However, our previous studies have revealed that DKK3 expression is predominantly observed in head and neck/oral squamous cell
carcinoma (HNSCC/OSCC). Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion. From these data, it was hypothesized
that DKK3 might exert an oncogenic function specific to HNSCC. In the present research, the DKK3 overexpression model was established, and its influences were investigated, together with molecular mechanism studies. The DKK3 expression profile in cancer cell lines was investigated, including
HNSCC/OSCC, esophageal, gastric, colorectal, pancreatic, prostatic, and lung cancers. DKK3 overexpression was performed in HNSCC-derived cells by transfection of expression plasmid. The effects of DKK3 overexpression were assessed on cellular proliferation, migration, invasion, and in vivo
tumor growth. The molecular mechanism of DKK3 overexpression was investigated by Western blotting and microarray analysis. DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc. However, reporter
assays did not show TCF/LEF activation, suggesting that the increased malignant property of cancer cells was not driven by the Wnt/β-catenin pathway. For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt
(S473) and c-Jun (Ser63) was elevated. The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion. From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration,
and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K‐Akt signaling.
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Head and neck squamous cell carcinoma (HNSCC);
Document Type: Research Article
Department of Oral Pathology and Bone Metabolism, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Department of Molecular and Developmental Biology, Kawasaki Medical School, Kurashiki, Okayama, Japan
Department of Biochemistry, Kawasaki Medical School, Kurashiki, Okayama, Japan
Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Okayama, Japan
School of Dentistry and Health Sciences, Charles Sturt University, Orange, New South Wales, Australia
Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
Publication date: January 19, 2018
This article was made available online on May 4, 2017 as a Fast Track article with title: "DKK3 Overexpression Increases Malignant Properties of Head and Neck Squamous Cell Carcinoma Cells".
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From Volume 23, Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics is Open Access under the terms of the Creative Commons CC BY-NC-ND license.