@Article{096504017X14926874596386,
AUTHOR = {Naoki Katase, Shin-Ichiro Nishimatsu, Akira Yamauchi, Masahiro Yamamura, Kumiko Terada, Masumi Itadani, Naoko Okada, Nur Mohammad Monsur Hassan, Hitoshi Nagatsuka, 
Tohru Ikeda, Tsutomu Nohno, Shuichi Fujita},
TITLE = {DKK3 Overexpression Increases the Malignant Properties  of Head and Neck Squamous Cell Carcinoma Cells},
JOURNAL = {Oncology Research},
VOLUME = {26},
YEAR = {2018},
NUMBER = {1},
PAGES = {45--58},
URL = {http://www.techscience.com/or/v26n1/56617},
ISSN = {1555-3906},
ABSTRACT = {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.},
DOI = {10.3727/096504017X14926874596386}
}