Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 54, Issue 3, Pages 1021-1032Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2018.4667
Keywords
head and neck squamous cell carcinoma; Dickkopf- related protein 3; phosphoinositide 3-kinase; protein kinase B; mitogen-activated protein kinase
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Funding
- MEXT KAKENHI [25861742, 16K11470]
- Kawasaki Medical School [25-S-3, 26-B-34, 27-B-063]
- KAWASAKI Foundation for Medical Science and Medical Welfare
- Wesco Scientific Promotion Foundation [2013-06]
- Takeda Science Foundation [2016-39]
- [2018047114]
- Grants-in-Aid for Scientific Research [25861742, 16K11470] Funding Source: KAKEN
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Dickkopf-related protein 3 (DKK3), which is a member of the Dickkopf WNT signaling pathway inhibitor family, is considered to be a tumor suppressor, due to its reduced expression in cancer cells and its ability to induce apoptosis when overexpressed by adenovirus. However, our previous study demonstrated alternative functions for DKK3 in head and neck squamous cell carcinoma (HNSCC). Our study reported that DKK3 expression was predominantly upregulated in HNSCC cell lines and tissue samples, and its expression was significantly correlated with poor prognosis. Furthermore, DKK3 overexpression in HNSCC cells significantly increased cancer cell proliferation, migration, invasion and in vivo tumor growth. These data have led to the hypothesis that DKK3 may exert oncogenic functions and may increase the malignant properties of HNSCC. The present study established a stable DKK3 knockdown cell line (HSC-3 shDKK3) using lentivirus-mediated short hairpin RNA, and assessed its effects on cancer cell behavior using MTT, migration and invasion assays. In addition, its effects on in vivo tumor growth were assessed using a xenograft model. Furthermore, the molecular mechanisms underlying the effects of DKK3 knockdown were investigated by microarray analysis, pathway analysis and western blotting. Compared with control cells, HSC-3 shDKK3 cells exhibited significantly reduced proliferation, migration and invasion, and formed significantly smaller tumor masses when subcutaneously transplanted into nude mice. In addition, in HSC-3 shDKK3 cells, the expression levels of phosphorylated (p)-protein kinase B (Akt) (Ser473), p-phosphoinositide 3-kinase (PI3K) p85 (Tyr467), p-PI3K p55 (Try199), p-3-phosphoinositide-dependent protein kinase-1 (PDK1) (Ser241) and total p38 mitogen-activated protein kinase (MAPK) were reduced. Furthermore, phosphorylation of mechanistic target of rapamycin (mTOR) (Ser2448) was slightly decreased in HSC-3 shDKK3 cells, which may be due to the increased expression of DEP domain-containing mTOR-interacting protein. Conversely, DKK3 overexpression in HSC-3 shDKK3 cells rescued cellular proliferation, migration and invasion. With regards to expression levels, p-PI3K and p-PDK1 expression was not altered, whereas mTOR and p-p38 MAPK expression was elevated. These data supported the hypothesis and indicated that DKK3 may contribute to the malignant phenotype of HNSCC cells via the PI3K/Akt/mTOR and MAPK signaling pathways.
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