PMID- 30569110
OWN - NLM
STAT- MEDLINE
DCOM- 20190520
LR  - 20211209
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 54
IP  - 3
DP  - 2019 Mar
TI  - DKK3 knockdown confers negative effects on the malignant potency of head and neck 
      squamous cell carcinoma cells via the PI3K/Akt and MAPK signaling pathways.
PG  - 1021-1032
LID - 10.3892/ijo.2018.4667 [doi]
AB  - 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.
FAU - Katase, Naoki
AU  - Katase N
AD  - Department of Oral Pathology, Institute of Biomedical Sciences, Nagasaki 
      University, Nagasaki, Nagasaki 852‑8588, Japan.
FAU - Nishimatsu, Shin-Ichiro
AU  - Nishimatsu SI
AD  - Department of Molecular and Developmental Biology, Kawasaki Medical School, 
      Kurashiki, Okayama 701‑0192, Japan.
FAU - Yamauchi, Akira
AU  - Yamauchi A
AD  - Department of Biochemistry, Kawasaki Medical School, Kurashiki, Okayama 701‑0192, 
      Japan.
FAU - Yamamura, Masahiro
AU  - Yamamura M
AD  - Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Okayama 
      701‑0192, Japan.
FAU - Fujita, Shuichi
AU  - Fujita S
AD  - Department of Oral Pathology, Institute of Biomedical Sciences, Nagasaki 
      University, Nagasaki, Nagasaki 852‑8588, Japan.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20181214
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Chemokines)
RN  - 0 (DKK3 protein, human)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Movement
MH  - Cell Proliferation
MH  - Chemokines
MH  - Computational Biology
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/deficiency/*genetics/*metabolism
MH  - *MAP Kinase Signaling System/genetics
MH  - Mice, Nude
MH  - Microarray Analysis
MH  - Neoplasm Invasiveness
MH  - Phosphatidylinositol 3-Kinases/genetics/*metabolism
MH  - Prognosis
MH  - Proto-Oncogene Proteins c-akt/genetics/*metabolism
MH  - Signal Transduction/genetics
MH  - Squamous Cell Carcinoma of Head and Neck/genetics/metabolism/*physiopathology
MH  - TOR Serine-Threonine Kinases/metabolism
OTO - NOTNLM
OT  - head and neck squamous cell carcinoma
OT  - Dickkopfrelated protein 3
OT  - phosphoinositide 3-kinase
OT  - protein kinase B
OT  - mitogen-activated protein kinase
EDAT- 2018/12/21 06:00
MHDA- 2019/05/21 06:00
CRDT- 2018/12/21 06:00
PHST- 2018/05/16 00:00 [received]
PHST- 2018/10/12 00:00 [accepted]
PHST- 2018/12/21 06:00 [pubmed]
PHST- 2019/05/21 06:00 [medline]
PHST- 2018/12/21 06:00 [entrez]
AID - 10.3892/ijo.2018.4667 [doi]
PST - ppublish
SO  - Int J Oncol. 2019 Mar;54(3):1021-1032. doi: 10.3892/ijo.2018.4667. Epub 2018 Dec 
      14.